U.S. patent application number 11/060561 was filed with the patent office on 2006-02-02 for poly-heterocyclic compounds and their use as metabotropic glutamate receptor antagonists.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Jalaj Arora, Louise Edwards, Bjorn Holm, Methvin Isaac, Annika Kers, Abdelmalik Slassi, Karin Staaf, Tomislav Stefanac, David Wensbo, Tao Xin.
Application Number | 20060025414 11/060561 |
Document ID | / |
Family ID | 34886130 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060025414 |
Kind Code |
A1 |
Arora; Jalaj ; et
al. |
February 2, 2006 |
Poly-heterocyclic compounds and their use as metabotropic glutamate
receptor antagonists
Abstract
The present invention relates to new compounds of formula I,
##STR1## wherein P, Q, X.sup.1, X.sup.2, X.sup.3, X.sup.4 X.sup.5,
X.sup.6, R.sup.1, R.sup.2, R.sup.3, m, n, and p are as defined as
in formula I, or salts, or hydrates thereof, processes for their
preparation and new intermediates used in the preparation thereof,
pharmaceutical compositions containing said compounds and to the
use of said compounds in therapy.
Inventors: |
Arora; Jalaj; (Mississauga,
CA) ; Edwards; Louise; (Mississauga, CA) ;
Isaac; Methvin; (Mississauga, CA) ; Kers; Annika;
(Sodertalje, SE) ; Staaf; Karin; (Hagersten,
SE) ; Slassi; Abdelmalik; (Mississauga, CA) ;
Stefanac; Tomislav; (Mississauga, CA) ; Wensbo;
David; (Grodinge, SE) ; Xin; Tao;
(Mississauga, CA) ; Holm; Bjorn; (Molndal,
SE) |
Correspondence
Address: |
BIRCH, STEWART, KOLASCH & BIRCH, LLP
P.O. BOX 747
8110 GATEHOUSE ROAD, SUITE 500 EAST
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
AstraZeneca AB
NPS Pharmaceuticals Inc.
|
Family ID: |
34886130 |
Appl. No.: |
11/060561 |
Filed: |
February 18, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60545292 |
Feb 18, 2004 |
|
|
|
Current U.S.
Class: |
514/235.5 ;
514/253.09; 544/124; 544/360 |
Current CPC
Class: |
A61P 19/06 20180101;
C07D 403/14 20130101; A61P 17/02 20180101; A61P 25/14 20180101;
A61P 3/04 20180101; A61P 3/10 20180101; A61P 27/16 20180101; A61P
43/00 20180101; A61P 19/02 20180101; A61P 25/22 20180101; A61P
21/04 20180101; A61P 25/18 20180101; A61P 27/02 20180101; A61P
29/00 20180101; A61P 1/00 20180101; A61P 25/28 20180101; C07D
413/14 20130101; A61P 25/00 20180101; A61P 25/16 20180101; A61P
27/06 20180101; A61P 25/24 20180101; A61P 25/08 20180101; A61P 9/10
20180101; A61P 3/00 20180101; C07D 401/14 20130101; C07D 413/04
20130101; A61P 25/06 20180101; C07D 401/04 20130101 |
Class at
Publication: |
514/235.5 ;
514/253.09; 544/360; 544/124 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/496 20060101 A61K031/496; C07D 413/14
20060101 C07D413/14; C07D 403/14 20060101 C07D403/14 |
Claims
1. A compound according to formula I ##STR15## wherein P is
selected from aryl and heteroaryl; R.sup.1 is attached to P via a
carbon atom on ring P and is selected from the group consisting of
hydroxy, halo, nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo,
C.sub.1-6alkyl, OC.sub.1-6alkyl, C.sub.2-6alkenyl,
OC.sub.2-6alkenyl, C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; X.sup.1 is selected from the
group consisting of: N, NR.sup.4 and CR.sup.4; X.sup.2 is selected
from the group consisting of: C and N; X.sup.3 is selected from the
group consisting of: CR.sup.4, N and O; X.sup.4 is selected from
the group consisting of: CR.sup.4, N, NR.sup.4 and O; X.sup.5 is
selected from the group consisting of: a bond, CR.sup.4R.sup.4',
NR.sup.4, O, S, SO and SO.sub.2; X.sup.6 is selected from the group
consisting of: CR.sup.4 and N; X.sup.7 is selected from the group
consisting of: C and N; R.sup.4 is independently selected from a
group consisting of hydrogen, hydroxy, C.sub.1-6alkyl,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.3-7cycloalkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; Q is selected the group
consisting of heterocycloalkyl and heteroaryl; R.sup.2 and R.sup.3
are independently selected from the group consisting of: hydroxy,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.1-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing atoms independently selected from C, N, O and S, which
ring may optionally be fused with a 5- or 6-membered ring
containing atoms independently selected from the group consisting
of C, N and O and wherein said ring and said fused ring may be
substituted by one or more A; wherein any C.sub.1-6alkyl, aryl, or
heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 may be
substituted by one or more A; A is selected from the group
consisting of: hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.0-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl; m is selected from 0, 1, 2, 3 or 4; n is selected from 0,
1, 2, 3 or 4; p is selected from 0, 1, 2, 3 or 4; and a salt or
hydrate thereof, with the proviso that the compound is not:
4,4'-(1,2-piperazinediyl)di-antipyrine;
4,4'-(1,2-piperazinediyl)di-antipyrine dihydrochloride; or
4,4'-(1,2-piperazinediyl)di-antipyrine dipicrate;
2. A compound according to claim 1 wherein m is selected from 1, 2,
3 or 4
3. A compound according to claim 1 wherein X.sup.7 is C.
4. A compound according to claim 1 wherein X.sup.5 is selected from
the group consisting of CR.sup.4R.sup.4', NR.sup.4, O, S, SO and
SO.sub.2.
5. A comound according to claim 1 wherein X.sup.3 is selected from
the group consisting of N and O.
6. A compound according to claim 1 wherein P is aryl.
7. A compound according to claim 6 wherein P is phenyl.
8. A compound according to claim 7 wherein m is selected from the
group consisting of 1 and 2.
9. A compound according to claim 1 wherein R.sup.1 is selected from
the group consisting of: halo, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.1-6alkyl, OC.sub.1-6alkyl,
C.sub.1-6alkylOR.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6.
10. A compound according to claim 9 wherein R is selected from the
group consisting of: Cl, F, Me, OMe, CF.sub.3, OCF.sub.3, and
CN.
11. A compound according to claim 1 wherein X.sup.2 is C.
12. A compound according to claim 11 wherein X.sup.1 is N or
CR.sup.4.
13. A compound according to claim 12 wherein when X.sup.3 is O,
X.sup.4 is N and when X.sup.3 is N, X.sup.4 is O.
14. A compound according to claim 1 wherein X.sup.2 is N.
15. A compound according to claim 14 wherein X.sup.1 is N.
16. A compound according to claim 15 wherein X.sup.3 is N and
X.sup.4 is N or CR.sup.4.
17. A compound according to claim 1 wherein X.sup.6 is N.
18. A compound according to claim 12 wherein X.sup.5 is selected
from the group consisting of a bond, CR.sup.4R.sup.4', NR.sup.4 and
O.
19. A compound according to claim 13 wherein X.sup.5 is selected
from the group consisting of a bond, O and NR.sup.4.
20. A compound according to claim 16 wherein X.sup.5 is selected
from the group consisting of O and CR.sup.4.
21. A compound according to claim 1 wherein R.sup.4 is selected
from the group consisting of: hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkylhalo and halo.
22. A compound according to claim 1 wherein Q is heteroaryl.
23. A compound according to claim 1 wherein Q is selected from the
group consisting of: ##STR16##
24. A compound according to claim 23 wherein Q is ##STR17##
25. A compound according to claim 1 wherein R.sup.2 and R.sup.3 are
independently selected from the group consisting of:
C.sub.1-4alkylhalo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl and C.sub.0-6alkylheteroaryl.
26. A compound according to claim 1 wherein A is selected from the
group consisting of: hydrogen, hydroxyl, halo, C.sub.0-6alkylcyano,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo.
27. A compound according to claim 1 selected from:
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidin-1-yl}-4-methyl-4H
[1,2,4]triazol-3-yl)-pyridine
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,-
4]triazol-3-yl)-morpholine
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-difluoromethoxy-phenyl)-4-m-
ethyl-4H-[1,2,4]triazol-3-yl]-morpholine
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-morpholine
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-morpholine
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-piperazine-1-carboxylic acid tert-butyl
ester
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl--
4H-1,2,4]triazol-3-yl)-piperazine
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-piperazine
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine-1-carboxylic acid
tert-butyl ester
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-4-methyl-piperazine
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phenyl]--
4-methyl-4H-1,2,4-triazol-3-yl}piperidine
4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H--
1,2,4-triazol-3-yl)pyridine
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4-
H-1,2,4-triazol-3-yl]piperidine
[4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H-
-1,2,4-triazol-3-yl)phenyl]dimethylamine
[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl--
4H-[1,2,4]triazol-3-yl)-benzyl]-dimethyl-amine
{2-[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethyl}-dimethyl-amine
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-morpholine (S)
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-morpholine
(R)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phen-
yl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine
(S)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phen-
yl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine
(R)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-
-4H-1,2,4-triazol-3-yl)pyridine
(S)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-
-4H-1,2,4-triazol-3-yl)pyridine
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopr-
opyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine,
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl--
4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine,
3-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H--
[1,2,4]triazol-3-yl)-pyridine,
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropy-
l-4H-[1,2,4]triazol-3-yl)-pyridine,
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadioazol-3-yl]-4-(5-pyridin-4-yl-4H-[1,2,-
4]triazol-3-yl)-morpholine,
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-3-yl-4H-1,-
2,4-triazol-3-yl)morpholine,
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-4-yl-4H-1,-
2,4-triazol-3-yl)morpholine,
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2,4-t-
riazol-3-yl)morpholine,
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-yl)-4-met-
hyl-4H-[1,2,4]triazol-3-yl]-morpholine,
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyridin-4-yl)--
4-methyl-4H-1,2,4-triazol-3-yl]morpholine,
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyridin-4-yl)-4-
-methyl-4H-1,2,4-triazol-3-yl]morpholine,
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-fluoropyridin-3-yl)-4-
-methyl-4H-1,2,4-triazol-3-yl]morpholine,
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(5-fluoropyridin-3-yl)-4-methyl--
4H-1,2,4-triazol-3-yl]morpholine,
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-2-yl-4H-
-1,2,4-triazol-3-yl)morpholine,
4-[5-(5-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-3-[3-(3-iodop-
henyl)-1,2,4-oxadiazol-5-yl]morpholine,
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1-
,2,4-triazol-3-yl)morpholine,
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl--
4H-1,2,4-triazol-3-yl]morpholine,
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2-
,4-triazol-3-yl)morpholine,
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-difluorophenyl)-4-methy-
l-4H-1,2,4-triazol-3-yl]morpholine,
3-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4-
H-1,2,4-triazol-3-yl)pyridine, and
4-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-methyl-4H-1,2-
,4-triazol-3-yl)pyridine.
28. A pharmaceutical composition comprising as active ingredient a
therapeutically effective amount of the compound according to claim
1, in association with one or more pharmaceutically acceptable
diluent, excipients and/or inert carrier.
29. The pharmaceutical composition according to claim 28, for use
in the treatment of mGluR 5 mediated disorders.
30. The compound according to claim 1, for use in therapy.
31. The compound according to claim 1, for use in treatment of
mGluR 5 mediated disorders.
32. Use of the compound according to claim 1, in the manufacture of
a medicament for the treatment of mGluR 5 mediated disorders.
33. A method of treatment of mGluR 5 mediated disorders, comprising
administrering to a mammal, including man in need of such
treatment, a therapeutically effective amount of the compound
according to claim 1.
34. The method according to claim 33, for use in treatment of
neurological disorders.
35. The method according to claim 33, for use in treatment of
psychiatric disorders.
36. The method according to claim 33, for use in treatment of
chronic and acute pain disorders.
37. The method according to claim 33, for use in treatment of
gastrointestinal disorders.
38. A method for inhibiting activation of mGluR 5 receptors,
comprising treating a cell containing said receptor with an
effective amount of the compound according to claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a new class of compounds,
to pharmaceutical compositions containing said compounds and to the
use of said compounds in therapy. The present invention further
relates to processes for the preparation of said compounds and to
new intermediates used in the preparation thereof.
BACKGROUND OF THE INVENTION
[0002] Glutamate is the major excitatory neurotransmitter in the
mammalian central nervous system (CNS). Glutamate produces its
effects on central neurons by binding to and thereby activating
cell surface receptors. These receptors have been divided into two
major classes, the ionotropic and metabotropic glutamate receptors,
based on the structural features of the receptor proteins, the
means by which the receptors transduce signals into the cell, and
pharmacological profiles.
[0003] The metabotropic glutamate receptors (mGluRs) are G
protein-coupled receptors that activate a variety of intracellular
second messenger systems following the binding of glutamate.
Activation of mGluRs in intact mammalian neurons elicits one or
more of the following responses: activation of phospholipase C;
increases in phosphoinositide (PI) hydrolysis; intracellular
calcium release; activation of phospholipase D; activation or
inhibition of adenyl cyclase; increases or decreases in the
formation of cyclic adenosine monophosphate (cAMP); activation of
guanylyl cyclase; increases in the formation of cyclic guanosine
monophosphate (cGMP); activation of phospholipase A.sub.2;
increases in arachidonic acid release; and increases or decreases
in the activity of voltage- and ligand-gated ion channels. Schoepp
et al., Trends Pharmacol. Sci. 14:13 (1993), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995),
Bordi and Ugolini, Prog. Neurobiol. 59:55 (1999).
[0004] Eight distinct mGluR subtypes, termed mGluR1 through mGluR8,
have been identified by molecular cloning. Nakanishi, Neuron
13:1031 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel
et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity
occurs via expression of alternatively spliced forms of certain
mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al.,
BBRC 199:1136 (1994), Joly et al., J. Neurosci. 15:3970 (1995).
[0005] Metabotropic glutamate receptor subtypes may be subdivided
into three groups, Group I, Group II, and Group III mGluRs, based
on amino acid sequence homology, the second messenger systems
utilized by the receptors, and by their pharmacological
characteristics. Group I mGluR comprises mGluR1, mGluR5 and their
alternatively spliced variants. The binding of agonists to these
receptors results in the activation of phospholipase C and the
subsequent mobilization of intracellular calcium.
Neurological, Psychiatric and Pain Disorders.
[0006] Attempts at elucidating the physiological roles of Group I
mGluRs suggest that activation of these receptors elicits neuronal
excitation. Various studies have demonstrated that Group I mGluRs
agonists can produce postsynaptic excitation upon application to
neurons in the hippocampus, cerebral cortex, cerebellum, and
thalamus, as well as other CNS regions. Evidence indicates that
this excitation is due to direct activation of postsynaptic mGluRs,
but it also has been suggested that activation of presynaptic
mGluRs occurs, resulting in increased neurotransmitter release.
Baskys, Trends Pharmacol. Sci. 15:92 (1992), Schoepp, Neurochem.
Int. 24:439 (1994), Pin et al., Neuropharmacology 34:1 (1995),
Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).
[0007] Metabotropic glutamate receptors have been implicated in a
number of normal processes in the mammalian CNS. Activation of
mGluRs has been shown to be required for induction of hippocampal
long-term potentiation and cerebellar long-term depression. Bashir
et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740
(1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377
(1994). A role for mGluR activation in nociception and analgesia
also has been demonstrated. Meller et al., Neuroreport 4: 879
(1993), Bordi and Ugolini, Brain Res. 871:223 (1999). In addition,
mGluR activation has been suggested to play a modulatory role in a
variety of other normal processes including synaptic transmission,
neuronal development, apoptotic neuronal death, synaptic
plasticity, spatial learning, olfactory memory, central control of
cardiac activity, waking, motor control and control of the
vestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et
al., Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417
(1995).
[0008] Further, Group I metabotropic glutamate receptors have been
suggested to play roles in a variety of acute and chronic
pathophysiological processes and disorders affecting the CNS. These
include stroke, head trauma, anoxic and ischemic injuries,
hypoglycemia, epilepsy, neurodegenerative disorders such as
Alzheimer's disease, psychiatric disorders and pain. Schoepp et
al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life
Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31
(1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al.,
J. Med. Chem. 38:1417 (1995), Spooren et al., Trends Pharmacol.
Sci. 22:331 (2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43
(2002), Neugebauer Pain 98:1 (2002). Much of the pathology in these
conditions is thought to be due to excessive glutamate-induced
excitation of CNS neurons. Because Group I mGluRs appear to
increase glutamate-mediated neuronal excitation via postsynaptic
mechanisms and enhanced presynaptic glutamate release, their
activation probably contributes to the pathology. Accordingly,
selective antagonists of Group I mGluR receptors could be
therapeutically beneficial in all conditions underlain by excessive
glutamate-induced excitation of CNS neurons, specifically as
neuroprotective agents, analgesics or anticonvulsants.
[0009] Recent advances in the elucidation of the neurophysiological
roles of metabotropic glutamate receptors generally and Group I in
particular, have established these receptors as promising drug
targets in the therapy of acute and chronic neurological and
psychiatric disorders and chronic and acute pain disorders.
Gastro Intestinal Disorders
[0010] The lower esophageal sphincter (LES) is prone to relaxing
intermittently. As a consequence, fluid from the stomach can pass
into the esophagus since the mechanical barrier is temporarily lost
at such times, an event hereinafter referred to as "G.I. reflux".
Gastro-esophageal reflux disease (GERD) is the most prevalent upper
gastrointestinal tract disease. Current pharmacotherapy aims at
reducing gastric acid secretion, or at neutralizing acid in the
esophagus. The major mechanism behind G.I. reflux has been
considered to depend on a hypotonic lower esophageal sphincter.
However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N.
Amer. 19, pp. 517-535, has shown that most reflux episodes occur
during transient lower esophageal sphincter relaxations (TLESRs),
i.e. relaxations not triggered by swallows. It has also been shown
that gastric acid secretion usually is normal in patients with
GERD.
[0011] The novel compounds according to the present invention are
assumed to be useful for the inhibition of transient lower
esophageal sphincter relaxations (TLESRs) and thus for treatment of
gastro-esophageal reflux disorder (GERD).
[0012] The wording "TLESR", transient lower esophageal sphincter
relaxations, is herein defined in accordance with Mittal, R. K,
Holloway, R. H., Penagini, R., Blackshaw, L. A., Dent, J, 1995;
Transient lower esophageal sphincter relaxation. Gastroenterology
109, pp. 601-610.
[0013] The wording "G.I. reflux" is herein defined as fluid from
the stomach being able to pass into the esophagus, since the
mechanical barrier is temporarily lost at such times.
[0014] The wording "GERD", gastro-esophageal reflux disease, is
herein defined in accordance with van Heerwarden, M A., Smout A. J.
P. M, 2000; Diagnosis of reflux disease. Bailliere's Clin.
Gastroenterol. 14, pp. 759-774.
[0015] Because of their physiological and pathophysiological
significance, there is a need for new potent mGluR agonists and
antagonists that display a high selectivity for mGluR subtypes,
particularly the Group I receptor subtype.
SUMMARY OF THE INVENTION
[0016] In one aspect of the invention there is provided a compound
according to formula I ##STR2## wherein [0017] P is selected from
aryl and heteroaryl; [0018] R.sup.1 is attached to P via a carbon
atom on ring P and is selected from the group consisting of:
hydroxy, halo, nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo,
C.sub.1-6alkyl, OC.sub.1-6alkyl, C.sub.2-6alkenyl,
OC.sub.2-6alkenyl, C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; [0019] X.sup.1 is selected from
the group consisting of: N, NR.sup.4 and CR.sup.4; [0020] X.sup.2
is selected from the group consisting of: C and N; [0021] X.sup.3
is selected from the group consisting of: CR.sup.4, N and O; [0022]
X.sup.4 is selected from the group consisting of: CR.sup.4, N,
NR.sup.4 and O; [0023] X.sup.5 is selected from the group
consisting of: a bond, CR.sup.4R.sup.4', NR.sup.4, O, S, SO and
SO.sub.2; [0024] X.sup.6 is selected from the group consisting of:
CR.sup.4 and N; [0025] X.sup.7 is selected from the group
consisting of: C and N; [0026] R.sup.4 is independently selected
from a group consisting of hydrogen, hydroxy, C.sub.1-6alkyl,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.3-7cycloalkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; [0027] Q is selected the group
consisting of heterocycloalkyl and heteroaryl; [0028] R.sup.2 and
R.sup.3 are independently selected from the group consisting of:
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.1-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing atoms independently selected from C, N, O and S, which
ring may optionally be fused with a 5- or 6-membered ring
containing atoms independently selected from the group consisting
of C, N and O and wherein said ring and said fused ring may be
substituted by one or more A; [0029] wherein any C.sub.1-6alkyl,
aryl, or heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 may
be substituted by one or more A; [0030] A is selected from the
group consisting of: hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.0-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; [0031] R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl; [0032] m is selected from 0, 1, 2, 3 or 4; [0033] n is
selected from 0, 1, 2, 3 or 4; [0034] p is selected from 0, 1, 2, 3
or 4; and [0035] a salt or hydrate thereof.
[0036] In a further aspect of the invention there is provided
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula I and a pharmaceutically acceptable
diluent, excipients and/or inert carrier.
[0037] In yet a further aspect of the invention there is provided a
pharmaceutical composition comprising a compound of formula I for
use in the treatment of mGluR5 receptor mediated disorders, and for
use in the treatment of neurological disorders, psychiatric
disorders, gastrointestinal disorders and pain disorders.
[0038] In still a further aspect of the invention there is provided
the compound of formula I for use in therapy, especially for the
treatment of mGluR5 receptor mediated disorders, and for the
treatment of neurological disorders, psychiatric disorders,
gastrointestinal disorders and pain disorders.
[0039] A further aspect of the invention is the use of a compound
according to formula X for the manufacture of a medicament for the
treatment or prevention of obesity and obesity related conditions,
as well as treating eating disorders by inhibition of excessive
food intake and the resulting obesity and complications associated
therewith.
[0040] In another aspect of the invention there is provided
processes for the preparation of compounds of formula I and the
intermediates used in the preparation thereof.
[0041] These and other aspects of the present invention are
described in greater detail herein below.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The object of the present invention is to provide compounds
exhibiting an activity at metabotropic glutamate receptors
(mGluRs), especially at the mGluR5 receptors.
[0043] Listed below are definitions of various terms used in the
specification and claims to describe the present invention.
[0044] For the avoidance of doubt it is to be understood that where
in this specification a group is qualified by `hereinbefore
defined`, `defined hereinbefore` or `defined above` said group
encompasses the first occurring and broadest definition as well as
each and all of the other definitions for that group.
[0045] For the avoidance of doubt it is to be understood that in
this specification `C.sub.1-6` means a carbon group having 1, 2, 3,
4, 5 or 6 carbon atoms. Similarly `C.sub.1-3` means a carbon group
having 1, 2, or 3 carbon atoms
[0046] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers indicates that the group is
absent.
[0047] In this specification, unless stated otherwise, the term
"alkyl" includes both straight and branched chain alkyl groups and
may be, but are not limited to methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl,
neo-pentyl, n-hexyl or i-hexyl, t-hexyl. The term C.sub.1-3alkyl
has 1 to 3 carbon atoms and may be methyl, ethyl, n-propyl or
i-propyl.
[0048] In this specification, unless stated otherwise, the term
"cycloalkyl" refers to an optionally substituted, saturated cyclic
hydrocarbon ring system. The term "C.sub.3-7cycloalkyl" may be
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
[0049] In this specification, unless stated otherwise, the term
"alkoxy" includes both straight or branched alkoxy groups.
C.sub.1-3alkoxy may be, but is not limited to methoxy, ethoxy,
n-propoxy or i-propoxy.
[0050] In this specification, unless stated otherwise, the term
"bond" may be a saturated or unsaturated bond.
[0051] In this specification, unless stated otherwise, the term
"halo" and "halogen" may be fluoro, chloro, bromo or iodo.
[0052] In this specification, unless stated otherwise, the term
"alkylhalo" means an alkyl group as defined above, which is
substituted with halo as described above. The term
"C.sub.1-6alkylhalo" may include, but is not limited to
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl or bromopropyl. The term "OC.sub.1-6alkylhalo" may
include, but is not limited to fluoromethoxy, difluoromethoxy,
trifluoromethoxy, fluoroethoxy or difluoroethoxy.
[0053] In this specification, unless stated otherwise, the term
"alkenyl" includes both straight and branched chain alkenyl groups.
The term "C.sub.2-6alkenyl" refers to an alkenyl group having 2 to
6 carbon atoms and one or two double bonds, and may be, but is not
limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl,
crotyl, pentenyl, i-pentenyl and hexenyl.
[0054] In this specification, unless stated otherwise, the term
"alkynyl" includes both straight and branched chain alkynyl groups.
The term C.sub.2-6alkynyl having 2 to 6 carbon atoms and one or two
triple bonds, and may be, but is not limited to ethynyl, propargyl,
butynyl, i-butynyl, pentynyl, i-pentynyl and hexynyl.
[0055] In this specification unless otherwise stated the term
"aryl" refers to an optionally substituted monocyclic or bicyclic
hydrocarbon ring system containing at least one unsaturated
aromatic ring. Examples and suitable values of the term "aryl" are
phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and
indenyl.
[0056] In this specification, unless stated otherwise, the term
"heteroaryl" refers to an optionally substituted monocyclic or
bicyclic unsaturated, ring system containing at least one
heteroatom selected independently from N, O or S. Examples of
"heteroaryl" may be, but are not limited to thiophene, thienyl,
pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl,
oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolonyl,
oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl,
benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,
tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl,
pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl,
oxazolopyridyl, thiazolopyridyl, pyridyl, imidazopyridazinyl,
oxazolopyridazinyl, thiazolopyridazinyl and purinyl.
[0057] In this specification, unless stated otherwise, the term
"alkylaryl", "alkylheteroaryl" and "alkylcycloalkyl" refer to a
substituent that is attached via the alkyl group to an aryl,
heteroaryl and cycloalkyl group.
[0058] In this specification, unless stated otherwise, the term
"heterocycloalkyl" refers to an optionally substituted, saturated
cyclic hydrocarbon ring system wherein one or more of the carbon
atoms are replaced with heteroatom. The term "heterocycloalkyl"
includes but is not limited to pyrrolidine, tetrahydrofuran,
tetrahydrothiophene, piperidine, piperazine, morpholine,
thiomorpholine, tetrahydropyran, tetrahydrothiopyran.
[0059] In this specification, unless stated otherwise the term "5-
or 6-membered ring containing atoms independently selected from C,
N, O or S", includes aromatic and heteroaromatic rings as well as
carbocyclic and heterocyclic rings, which may be saturated,
partially saturated or unsaturated. Examples of such rings may be,
but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,
thiazolyl, thienyl, imidazolyl, imidazolidinyl, imidazolinyl,
triazolyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl
and cyclohexenyl.
[0060] In this specification, unless stated otherwise, the term
".dbd.NR.sup.5" and ".dbd.NOR.sup.5" include imino- and
oximo-groups carrying an R.sup.5 substituent and may be, or be part
of, groups including, but not limited to iminoalkyl, iminohydroxy,
iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.
[0061] In the case where a subscript is the integer 0 (zero) the
group to which the subscript refers, indicates that the group is
absent, i.e. there is a direct bond between the groups. In this
specification unless stated otherwise the term "fused rings" refers
to two rings which share 2 common atoms.
[0062] In this specification, unless stated otherwise, the term
"bridge" means a molecular fragment, containing one or more atoms,
or a bond, which connects two remote atoms in a ring, thus forming
either bi- or tricyclic systems.
[0063] One embodiment of the invention relates to compounds of
Formula I ##STR3## wherein [0064] P is selected from aryl and
heteroaryl; [0065] R.sup.1 is attached to P via a carbon atom on
ring P and is selected from the group consisting of: hydroxy, halo,
nitro, C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo, C.sub.1-6alkyl,
OC.sub.1-6alkyl, C.sub.2-6alkenyl, OC.sub.2-6alkenyl,
C.sub.2-6alkynyl, OC.sub.2-6alkynyl,
C.sub.0-6alkylC.sub.3-6cycloalkyl,
OC.sub.0-6alkylC.sub.3-6cycloalkyl, C.sub.0-6alkylaryl,
OC.sub.0-6alkylaryl, CHO, (CO)R.sup.5, O(CO)R.sup.5, O(CO)OR.sup.5,
O(CNR.sup.5)OR.sup.5, C.sub.1-6alkylOR.sup.5,
OC.sub.2-6alkylOR.sup.5, C.sub.1-6alkyl(CO)R.sup.5,
OC.sub.1-6alkyl(CO)R.sup.5, C.sub.0-6alkylCO.sub.2R.sup.5,
OC.sub.1-6alkylCO.sub.2R.sup.5, C.sub.0-6alkylcyano,
OC.sub.2-6alkylcyano, C.sub.0-6alkylNR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5R.sup.6, C.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, C.sub.0-6alkylSR.sup.5,
OC.sub.2-6alkylSR.sup.5, C.sub.0-6alkyl(SO)R.sup.5,
OC.sub.2-6alkyl(SO)R.sup.5, C.sub.0-6alkylSO.sub.2R.sup.5,
OC.sub.2-6alkylSO.sub.2R.sup.5,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6, NR.sup.5OR.sup.6,
C.sub.0-6alkylNR.sup.5(CO)OR.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)OR.sup.6, SO.sub.3R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; [0066] X.sup.1 is selected from
the group consisting of: N, NR.sup.4 and CR.sup.4; [0067] X.sup.2
is selected from the group consisting of: C and N; [0068] X.sup.3
is selected from the group consisting of: CR.sup.4, N and O; [0069]
X.sup.4 is selected from the group consisting of: CR.sup.4, N,
NR.sup.4 and O; [0070] X.sup.5 is selected from the group
consisting of: a bond, CR.sup.4R.sup.4', NR.sup.4, O, S, SO and
SO.sub.2; [0071] X.sup.6 is selected from the group consisting of:
CR.sup.4 and N; [0072] X.sup.7 is selected from the group
consisting of: C and N; [0073] R.sup.4 is independently selected
from a group consisting of hydrogen, hydroxy, C.sub.1-6alkyl,
C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.3-7cycloalkyl, O(CO)C.sub.1-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, OC.sub.1-4alkyl, C.sub.1-4alkylOR.sup.5
and C.sub.0-4alkylNR.sup.5R.sup.6; [0074] Q is selected the group
consisting of heterocycloalkyl and heteroaryl; [0075] R.sup.2 and
R.sup.3 are independently selected from the group consisting of:
hydroxy, C.sub.0-6alkylcyano, oxo, .dbd.NR.sup.5, .dbd.NOR.sup.5,
C.sub.1-4alkylhalo, halo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl, C.sub.0-6alkylheteroaryl,
C.sub.1-6alkylcycloalkyl, C.sub.0-6alkylheterocycloalkyl,
OC.sub.1-4alkyl, OC.sub.0-6alkylaryl, O(CO)C.sub.1-4alkyl,
(CO)OC.sub.1-4alkyl, C.sub.0-4alkyl(S)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO)C.sub.0-4alkyl,
C.sub.1-4alkyl(SO.sub.2)C.sub.0-4alkyl, (SO)C.sub.0-4alkyl,
(SO.sub.2)C.sub.0-4alkyl, C.sub.1-4alkylOR.sup.5,
C.sub.0-4alkylNR.sup.5R.sup.6 and a 5- or 6-membered ring
containing atoms independently selected from C, N, O and S, which
ring may optionally be fused with a 5- or 6-membered ring
containing atoms independently selected from the group consisting
of C, N and O and wherein said ring and said fused ring may be
substituted by one or more A; [0076] wherein any C.sub.1-6alkyl,
aryl, or heteroaryl defined under R.sup.1, R.sup.2 and R.sup.3 may
be substituted by one or more A; [0077] A is selected from the
group consisting of: hydrogen, hydroxy, halo, nitro, oxo,
C.sub.0-6alkylcyano, C.sub.0-4alkylC.sub.3-6cycloalkyl,
C.sub.1-6alkyl, --OC.sub.1-6alkyl, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.2-6alkenyl, C.sub.0-3alkylaryl,
C.sub.0-6alkylOR.sup.5, OC.sub.2-6alkylOR.sup.5,
C.sub.0-6alkylSR.sup.5, OC.sub.2-6alkylSR.sup.5, (CO)R.sup.5,
O(CO)R.sup.5, OC.sub.2-6alkylcyano, OC.sub.1-6alkylCO.sub.2R.sup.5,
O(CO)OR.sup.5, OC.sub.1-6alkyl(CO)R.sup.5,
C.sub.1-6alkyl(CO)R.sup.5, NR.sup.5OR.sup.6,
C.sub.0-6NR.sup.5R.sup.6, OC.sub.2-6alkylNR.sup.5R.sup.6,
C.sub.0-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.1-6alkyl(CO)NR.sup.5R.sup.6,
OC.sub.2-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)R.sup.6,
C.sub.0-6alkylNR.sup.5(CO)NR.sup.5R.sup.6, O(CO)NR.sup.5R.sup.6,
C.sub.0-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)NR.sup.5R.sup.6,
C.sub.0-6alkylNR.sup.5(SO.sub.2)R.sup.6,
OC.sub.2-6alkylNR.sup.5(SO.sub.2)R.sup.6, SO.sub.3R.sup.5,
C.sub.1-6alkylNR.sup.5(SO.sub.2)NR.sup.5R.sup.6,
OC.sub.2-6alkyl(SO.sub.2)R.sup.5, C.sub.0-6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; [0078] R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl; [0079] m is selected from 0, 1, 2, 3 or 4; [0080] n is
selected from 0, 1, 2, 3 or 4; [0081] p is selected from 0, 1, 2, 3
or 4; and [0082] a salt or hydrate thereof.
[0083] Another embodiment the invention relates to the compounds:
[0084]
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidin-1-yl}-4-methyl-4H
[1,2,4]triazol-3-yl)-pyridine, [0085]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,-
4]triazol-3-yl)-morpholine, [0086]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-difluoromethoxy-phenyl)-4-m-
ethyl-4H-[1,2,4]triazol-3-yl]-morpholine, [0087]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-morpholine, [0088]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-morpholine, [0089]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-piperazine-1-carboxylic acid tert-butyl
ester, [0090]
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyrid-
in-4-yl-4H-1,2,4]triazol-3-yl)-piperazine, [0091]
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyri-
din-4-yl-4H-[1,2,4]triazol-3-yl)-piperazine, [0092]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine-1-carboxylic acid
tert-butyl ester, [0093]
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine, [0094]
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-4-methyl-piperazine, [0095]
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phenyl]--
4-methyl-4H-1,2,4-triazol-3-yl}piperidine, [0096]
4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H--
1,2,4-triazol-3-yl)pyridine, [0097]
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4-
H-1,2,4-triazol-3-yl]piperidine, [0098]
[4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H-
-1,2,4-triazol-3-yl)phenyl]dimethylamine, [0099]
[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl--
4H-[1,2,4]triazol-3-yl)-benzyl]-dimethyl-amine, [0100]
{2-[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-meth-
yl-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethyl}-dimethyl-amine, [0101]
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-
-yl-4H-[1,2,4]triazol-3-yl)-morpholine, [0102] (S)
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-morpholine, [0103]
(R)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phen-
yl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine, [0104]
(S)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phen-
yl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine, [0105]
(R)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-
-4H-1,2,4-triazol-3-yl)pyridine, [0106]
(S)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-
-4H-1,2,4-triazol-3-yl)pyridine, [0107]
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopr-
opyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine, [0108]
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl--
4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine, [0109]
3-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-methyl-4H--
[1,2,4]triazol-3-yl)-pyridine, [0110]
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4-cyclopropy-
l-4H-[1,2,4]triazol-3-yl)-pyridine, [0111]
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadioazol-3-yl]-4-(5-pyridin-4-yl-4H-[1,2,-
4]triazol-3-yl)-morpholine, [0112]
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-3-yl-4H-1,-
2,4-triazol-3-yl)morpholine, [0113]
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin-4-yl-4H-1,-
2,4-triazol-3-yl)morpholine, [0114]
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2,4-t-
riazol-3-yl)morpholine, [0115]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-yl)-4-met-
hyl-4H-[1,2,4]triazol-3-yl]-morpholine, [0116]
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyridin-4-yl)--
4-methyl-4H-1,2,4-triazol-3-yl]morpholine, [0117]
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyridin-4-yl)-4-
-methyl-4H-1,2,4-triazol-3-yl]morpholine, [0118]
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-fluoropyridin-3-yl)-4-
-methyl-4H-1,2,4-triazol-3-yl]morpholine, [0119]
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(5-fluoropyridin-3-yl)-4-methyl--
4H-1,2,4-triazol-3-yl]morpholine, [0120]
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-2-yl-4H-
-1,2,4-triazol-3-yl)morpholine, [0121]
4-[5-(5-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-3-[3-(3-iodop-
henyl)-1,2,4-oxadiazol-5-yl]morpholine, [0122]
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1-
,2,4-triazol-3-yl)morpholine, [0123]
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-4-methyl--
4H-1,2,4-triazol-3-yl]morpholine, [0124]
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-3-yl-4H-1,2-
,4-triazol-3-yl)morpholine, and [0125]
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-difluorophenyl)-4-methy-
l-4H-1,2,4-triazol-3-yl]morpholine.
[0126] This invention relates to polycyclic compounds of formula 1
having a variable P. In embodiments of the invention P is aryl. In
particular embodiments of the invention P is phenyl.
[0127] In embodiments of the invention m is 1 or 2.
[0128] In particular embodiments of the invention P is phenyl
having one or two substituents R.sup.1. In more particular
embodiments of the invention, when there is one substituent R.sup.1
the substituent in located at the 3-position of the phenyl relative
to X.sup.2. In other particular embodiments of the invention when
there are two substituents R.sup.1, the substituents are located at
the 2- and 5-positions of the phenyl, relative to X.sup.2.
[0129] In another embodiment of the invention R.sup.1 is selected
from the group consisting of: hydrogen, halo, C.sub.1-6alkylhalo,
OC.sub.1-6alkylhalo, C.sub.1-6alkyl, OC.sub.1-6alkyl,
C.sub.1-6alkylOR.sup.5, C.sub.0-6alkylcyano,
C.sub.0-6alkylNR.sup.5R.sup.6. In still another embodiment of the
invention R.sup.1 is selected from the group consisting Cl, F, Me,
OMe, CF.sub.3, OCF.sub.3, and CN. In yet another embodiment of the
invention R.sup.1 is Cl.
[0130] In embodiments of the invention X.sup.7 is C. In other
embodiments of the invention X.sup.2 is C. In preferred embodiments
of the invention at least one of X.sup.2 and X.sup.7 is C.
[0131] In another embodiment of the invention X3 is selected from N
and O.
[0132] The invention further relates to compounds of Formula I
wherein X.sup.2 is C. Embodiments of the invention include those
where X.sup.1 is N or CR.sup.4. In a further embodiment of the
invention when X.sup.3 is O, X.sup.4 is N and when X.sup.3 is N,
X.sup.4 is O.
[0133] In another embodiment of the invention X.sup.2 is N. In a
further embodiment of the invention X.sup.1 is N. In still a
further embodiment of the invention X.sup.3 is N and X.sup.4 are N
or CR.sup.4.
[0134] In another embodiment of the invention X.sup.5 is selected
from the group consisting of CR.sup.4R.sup.4', NR.sup.4, O, S, SO
and SO.sub.2. In a further embodiment of the invention X.sup.5 is
selected from the group consisting of CR.sup.4R.sup.4', NR.sup.4
and O. In yet a further embodiment of the invention X.sup.5 is
selected from the group consisting of O and NR.sup.4.
[0135] Particular embodiments of the invention include those where
the ring containing X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
selected such that the ring formed is a tetrazole, triazole,
oxadiazole, oxazole, isoxazole, or imidazole ring. Preferably the
ring is tetrazole, oxadiazole or isoxazole.
[0136] In embodiments of the invention X.sup.6 is N. In further
embodiments of the invention X.sup.5 is selected from O and
NR.sup.4. In still further embodiments of the invention X.sup.5 is
selected from CR.sup.4R.sup.4'.
[0137] In particular embodiments of the invention when the ring
containing X.sup.1, X.sup.2, X.sup.3 and X.sup.4 is tetrazole,
X.sup.6 is N and X.sup.5 is CR.sup.4R.sup.4'. In another particular
embodiment of the invention when the ring containing X.sup.1,
X.sup.2, X.sup.3 and X.sup.4 is selected from, oxadiazole and
isoxazole, X.sup.6 is N and X.sup.5 is selected from O and
NR.sup.4.
[0138] In another embodiment of the invention R.sup.4 and R.sup.4'
are independently selected from the group consisting of: hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkylhalo and halo.
[0139] The present invention relates to compounds of formula 1 have
a ring Q. Embodiments of the invention include those where Q is
heteroaryl. In preferred embodiments Q is selected from the group
consisting of: ##STR4##
[0140] In a more preferred embodiment of the invention the ring Q
is ##STR5##
[0141] Embodiments of the invention include those where R.sup.1 and
R.sup.2 are selected from the group consisting of: hydrogen,
C.sub.1-4alkylhalo, C.sub.1-6alkyl, C.sub.3-6cycloalkyl,
C.sub.0-6alkylaryl and C.sub.0-6alkylheteroaryl.
[0142] In still another embodiment of the invention the variable
any C.sub.1-6alkyl, aryl, or heteroaryl defined under R.sup.1,
R.sup.2 and R.sup.3 may be substituted by one or more substituents
A. Particular embodiments of the invention include those where A is
selected from the group consisting of: hydrogen, hydroxyl, halo,
C.sub.0-6alkylcyano, C.sub.1-6alkyl, --OC.sub.1-6alkyl,
C.sub.1-6alkylhalo, OC.sub.1-6alkylhalo.
[0143] Embodiments of the invention include salt forms of the
compounds of Formula I. Salts for use in pharmaceutical
compositions will be pharmaceutically acceptable salts, but other
salts may be useful in the production of the compounds of Formula
I.
[0144] A suitable pharmaceutically acceptable salt of the compounds
of the invention is, for example, an acid-addition salt, for
example an inorganic or organic acid. In addition, a suitable
pharmaceutically acceptable salt of the compounds of the invention
is an alkali metal salt, an alkaline earth metal salt or a salt
with an organic base.
[0145] Other pharmaceutically acceptable salts and methods of
preparing these salts may be found in, for example, Remington's
Pharmaceutical Sciences (18.sup.th Edition, Mack Publishing Co.)
1990.
[0146] Some compounds of formula I may have chiral centres and/or
geometric isomeric centres (E- and Z-isomers), and it is to be
understood that the invention encompasses all such optical,
diastereoisomeric and geometric isomers.
[0147] The invention also relates to any and all tautomeric forms
of the compounds of Formula I.
[0148] The invention further relates to hydrate and solvate forms
of the compounds of Formula I.
Pharmaceutical Composition
[0149] According to one aspect of the present invention there is
provided a pharmaceutical composition comprising as active
ingredient a therapeutically effective amount of the compound of
Formula I, or salts, solvates or solvated salts thereof, in
association with one or more pharmaceutically acceptable diluent,
excipients and/or inert carrier.
[0150] The composition may be in a form suitable for oral
administration, for example as a tablet, pill, syrup, powder,
granule or capsule, for parenteral injection (including
intravenous, subcutaneous, intramuscular, intravascular or
infusion) as a sterile solution, suspension or emulsion, for
topical administration e.g. as an ointment, patch or cream or for
rectal administration e.g. as a suppository.
[0151] In general the above compositions may be prepared in a
conventional manner using one or more conventional excipients,
pharmaceutical acceptable diluents and/or inert carriers.
[0152] Suitable daily doses of the compounds of formula I in the
treatment of a mammal, including man are approximately 0.01 to 250
mg/kg bodyweight at peroral administration and about 0.001 to 250
mg/kg bodyweight at parenteral administration.
[0153] The typical daily dose of the active ingredients varies
within a wide range and will depend on various factors such as the
relevant indication, severity of the illness being treated, the
route of administration, the age, weight and sex of the patient and
the particular compound being used, and may be determined by a
physician.
Medical Use
[0154] It has been found that the compounds according to the
present invention, exhibit a high degree of potency and selectivity
for individual metabotropic glutamate receptor (mGluR) subtypes.
Accordingly, the compounds of the present invention are expected to
be useful in the treatment of conditions associated with excitatory
activation of mGluR5 and for inhibiting neuronal damage caused by
excitatory activation of mGluR5. The compounds may be used to
produce an inhibitory effect of mGluR5 in mammals, including
man.
[0155] The mGluR Group I receptor including mGluR5 are highly
expressed in the central and peripheral nervous system and in other
tissues. Thus, it is expected that the compounds of the invention
are well suited for the treatment of mGluR5-mediated disorders such
as acute and chronic neurological and psychiatric disorders,
gastrointestinal disorders, and chronic and acute pain
disorders.
[0156] The invention relates to compounds of Formula I, as defined
hereinbefore, for use in therapy.
[0157] The invention relates to compounds of Formula I, as defined
hereinbefore, for use in treatment of mGluR5-mediated
disorders.
[0158] The invention relates to compounds of Formula I, as defined
hereinbefore, for use in treatment of Alzheimer's disease senile
dementia, AIDS-induced dementia, Parkinson's disease, amylotropic
lateral sclerosis, Huntington's Chorea, migraine, epilepsy,
schizophrenia, depression, anxiety, acute anxiety, ophthalmological
disorders such as retinopathies, diabetic retinopathies, glaucoma,
auditory neuropathic disorders such as tinnitus, chemotherapy
induced neuropathies, post-herpetic neuralgia and trigeminal
neuralgia, tolerance, dependency, Fragile X, autism, mental
retardation, schizophrenia and Down's Syndrome.
[0159] The invention relates to compounds of Formula I, as defined
hereinbefore, for use in treatment of pain related to migraine,
inflammatory pain, neuropathic pain disorders such as diabetic
neuropathies, arthritis and rheumatoid diseases, low back pain,
post-operative pain and pain associated with various conditions
including angina, renal or biliary colic, menstruation, migraine
and gout.
[0160] The invention relates to compounds of Formula I as defined
hereinbefore, for use in treatment of stroke, head trauma, anoxic
and ischemic injuries, hypoglycemia, cardiovascular diseases and
epilepsy.
[0161] The present invention relates also to the use of a compound
of Formula I as defined hereinbefore, in the manufacture of a
medicament for the treatment of mGluR Group I receptor-mediated
disorders and any disorder listed above.
[0162] One embodiment of the invention relates to the use of a
compound according to Formula I in the treatment of
gastrointestinal disorders.
[0163] Another embodiment of the invention relates to the use of a
compound according to Formula I, for the manufacture of a
medicament for the inhibition of transient lower esophageal
sphincter relaxations, for the treatment of GERD, for the
prevention of G.I. reflux, for the treatment regurgitation,
treatment of asthma, treatment of laryngitis, treatment of lung
disease and for the management of failure to thrive.
[0164] A further embodiment of the invention is the use of a
compound according to Formula I for the manufacture of a medicament
for the treatment or prevention of functional gastrointestinal
disorders, such as functional dyspepsia (FD). Yet another aspect of
the invention is the use of a compound according to formula I for
the manufacture of a medicament for the treatment or prevention of
irritable bowel syndrome (IBS), such as constipation predominant
IBS, diarrhea predominant IBS or alternating bowel movement
predominant IBS. [0165] .sub.6alkyl(SO.sub.2)R.sup.5,
C.sub.0-6alkyl(SO)R.sup.5, OC.sub.2-6alkyl(SO)R.sup.5 and a 5- or
6-membered ring containing atoms independently selected from the
group consisting of C, N, O and S; [0166] R.sup.5 and R.sup.6 are
independently selected from, H, C.sub.1-6alkyl, C.sub.3-7cycloalkyl
and aryl; [0167] m is selected from 0, 1, 2, 3 or 4; [0168] n is
selected from 0, 1, 2, 3 or 4; [0169] p is selected from 0, 1, 2, 3
or 4; and [0170] a salt or hydrate thereof.
[0171] In a further aspect of the invention there is provided
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula I and a pharmaceutically acceptable
diluent, excipients and/or inert carrier.
[0172] In yet a further aspect of the invention there is provided a
pharmaceutical composition comprising a compound of formula I for
use in the treatment of mGluR5 receptor mediated disorders, and for
use in the treatment of neurological disorders, psychiatric
disorders, gastrointestinal disorders and pain disorders.
[0173] In still a further aspect of the invention there is provided
the compound of formula I for use in therapy, especially for the
treatment of mGluR5 receptor mediated disorders, and for the
treatment of neurological disorders, psychiatric disorders,
gastrointestinal disorders and pain disorders.
[0174] A further aspect of the invention is the use of a compound
according to formula I for the manufacture of a medicament for the
treatment or prevention of obesity and obesity related conditions,
as well as treating eating disorders by inhibition of excessive
food intake and the resulting obesity and complications associated
therewith.
[0175] In another aspect of the invention there is provided
processes for the preparation of compounds of formula I and the
intermediates used in the preparation thereof. These and other
aspects of the present invention are described in greater detail
herein below.
[0176] The invention also provides a method of treatment of
mGluR5-mediated disorders and any disorder listed above, in a
patient suffering from, or at risk of, said condition, which
comprises administering to the patient an effective amount of a
compound of Formula I, as hereinbefore defined.
[0177] The dose required for the therapeutic or preventive
treatment of a particular disorder will necessarily be varied
depending on the host treated, the route of administration and the
severity of the illness being treated.
[0178] In the context of the present specification, the term
"therapy" and "treatment" includes prevention or prophylaxis,
unless there are specific indications to the contrary. The terms
"therapeutic" and "therapeutically" should be construed
accordingly.
[0179] In this specification, unless stated otherwise, the term
"antagonist" and "inhibitor" shall mean a compound that by any
means, partly or completely, blocks the transduction pathway
leading to the production of a response by the ligand.
[0180] The term "disorder", unless stated otherwise, means any
condition and disease associated with metabotropic glutamate
receptor activity.
Non-Medical Use
[0181] In addition to their use in therapeutic medicine, the
compounds of Formula I, salts or hydrates thereof, are also useful
as pharmacological tools in the development and standardisation of
in vitro and in vivo test systems for the evaluation of the effects
of inhibitors of mGluR related activity in laboratory animals such
as cats, dogs, rabbits, monkeys, rats and mice, as part of the
search for new therapeutics agents.
Methods of Preparation
[0182] Another aspect of the present invention provides processes
for preparing compounds of Formula I, or salts or hydrates thereof.
Processes for the preparation of the compounds in the present
invention are described herein.
[0183] Throughout the following description of such processes it is
to be understood that, where appropriate, suitable protecting
groups will be added to, and subsequently removed from, the various
reactants and intermediates in a manner that will be readily
understood by one skilled in the art of organic synthesis.
Conventional procedures for using such protecting groups as well as
examples of suitable protecting groups are described, for example,
in "Protective Groups in Organic Synthesis", T. W. Green, P. G. M.
Wuts, Wiley-Interscience, New York, (1999). It is also to be
understood that a transformation of a group or substituent into
another group or substituent by chemical manipulation can be
conducted on any intermediate or final product on the synthetic
path toward the final product, in which the possible type of
transformation is limited only by inherent incompatibility of other
functionalities carried by the molecule at that stage to the
conditions or reagents employed in the transformation. Such
inherent incompatibilities, and ways to circumvent them by carrying
out appropriate transformations and synthetic steps in a suitable
order, will be readily understood to the one skilled in the art of
organic synthesis. Examples of transformations are given below, and
it is to be understood that the described transformations are not
limited only to the generic groups or substituents for which the
transformations are exemplified. References and descriptions on
other suitable transformations are given in "Comprehensive Organic
Transformations--A Guide to Functional Group Preparations" R. C.
Larock, VHC Publishers, Inc. (1989). References and descriptions of
other suitable reactions are described in textbooks of organic
chemistry, for example, "Advanced Organic Chemistry", March, 4th
ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill,
(1994). Techniques for purification of intermediates and final
products include for example, straight and reversed phase
chromatography on column or rotating plate, recrystallisation,
distillation and liquid-liquid or solid-liquid extraction, which
will be readily understood by the one skilled in the art. The
definitions of substituents and groups are as in formula I except
where defined differently. The term "room temperature" and "ambient
temperature" shall mean, unless otherwise specified, a temperature
between 16 and 25.degree. C.
[0184] The term "reflux" shall mean, unless otherwise stated, in
reference to an employed solvent a temperature at or above the
boiling point of named solvent.
Abbreviations
[0185] aq. Aqueous [0186] atm atmosphere [0187] BINAP
2,2'Bis(diphenylphosphino)-1,1'-binaphthyl [0188] Boc, BOC
tert-butoxycarbonyl [0189] CDIN,N'-Carbonyldiimidazole [0190] dba
Dibenzylideneacetone [0191] DCC N,N-Dicyclohexylcarbodiimide [0192]
DCM Dichloromethane [0193] DEA N,N-Diisopropylethylamine [0194]
DIBAL-H Diisobutylaluminum hydride [0195]
DICN,N'-Diisopropylcarbodiimide [0196] DMAP
N,N-Dimethyl-4-aminopyridine [0197] DMF Dimethylformamide [0198]
DMSO Dimethylsulfoxide [0199] DPPF
1,1'-Bis(diphenylphosphino)ferrocene [0200] EA or EtOAc Ethyl
acetate [0201] EDC, EDCI
N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride
[0202] Et Ethyl [0203] Et.sub.2O Diethyl ether [0204] EtI
Iodoethane [0205] EtOH Ethanol [0206] Et.sub.3N Triethylamine
[0207] Fmoc, FMOC 9-Fluorenylmethoxycarbonyl [0208] h hour(s)
[0209] HBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0210] HetAr Heteroaryl [0211] HOBt
N-Hydroxybenzotriazole [0212] HPLC high performance liquid
chromatography [0213] LCMS HPLC mass spec [0214] MCPBA
m-chlorbenzoic acid [0215] Me Methyl [0216] MeCN Acetonitrile
[0217] MeI Iodomethane [0218] MeMgCl methyl magnesium chloride
[0219] MeOH Methanol [0220] min Minutes [0221] NaOAc sodium acetate
[0222] nBu normal butyl [0223] nBuLi, n-BuLi 1-butyllithium [0224]
NCS N-chlorosuccinimide [0225] NMR nuclear magnetic resonance
[0226] o.n. over night [0227] OAc acetate [0228] OMs mesylate or
methane sulfonate ester [0229] OTstosylate, toluene sulfonate or
4-methylbenzene sulfonate ester [0230] PPTS pyridinium
p-toluenesulfonate [0231] pTsOH p-toluenesulfonic acid [0232] RT,
rt, r.t. room temperature [0233] sat. Saturated [0234] SPEsolid
phase extraction (usually containing silica gel) [0235] TBAF
tetrabutylammonium fluoride [0236] tBu, t-Bu tert-butyl [0237]
tBuOH, t-BuOH tert-butanol [0238] TEA Triethylamine [0239] THF
Tetrahydrofuran Preparation of Intermediates
[0240] The intermediates provided in synthetic paths given below,
are useful for further preparation of compounds of formula I. Other
starting materials are either commercially available or can be
prepared via methods described in the literature. The synthetic
pathways described below are non-limiting examples of preparations
that can be used. One of skill in the art would understand other
pathways might be used. Synthesis of Isoxazoles ##STR6##
[0241] Aldehydes of formula vi wherein X.sup.5 is as defined in
formula I may be used in the preparation of isoxazoles.
Commercially available acid derivatives of formula ii wherein
X.sup.5 is O, S, C, N--R.sup.2 and N-G.sup.2 (G.sup.2 is a
protecting group orthogonal to G.sup.1) may undergo N-protection to
yield compounds of formula iii wherein G.sup.1 is a protecting
group such as Boc or Fmoc using methods well known in the art. The
acid moiety in compounds of formula iii may be transformed into an
alkyl ester of formula iv, such as for example the methyl or ethyl
ester, which may be transformed to aldehydes of formula vi using a
mild reducing agent such as DIBAL-H in a solvent such as toluene at
low temperature, for example -78.degree. C. Higher temperatures or
stronger reducing agents may result in formation of the primary
alcohols of formula v, either exclusively or as a mixture with the
aldehydes of formula vi. Other functional groups such as the
primary alcohol in compounds of formula v, the nitrile in compounds
of formula vii and Weinreb amide moiety in compounds of formula
viii may be transformed into aldehydes of formula vi utilizing
procedures established in the art. Additionally, acids of formula
ii may be converted into nitrites of formula vii by methods known
in the art, for example by conversion of the acid to the primary
amide followed by dehydration to the nitrile.
[0242] Aldehydes of formula vi may be converted to oximes of
formula ix by treatment with hydroxylamine, in a solvent such as
pyridine, at a temperature between 0.degree. C. to room
temperature. Isoxazoles of formula x may be prepared by
chlorination of oximes of formula ix using a reagent such as
N-chlorosuccinimide (NCS), followed by 1,3-dipolar cycloaddition
with the appropriately R-substituted acetylenes, wherein R may be
(R.sup.1).sub.m--P or a masking group which may later be converted
to (R.sup.1).sub.m--P (Steven, R. V. et al. J. Am. Chem. Soc. 1986,
108, 1039). The isoxazole intermediate x can subsequently be
deprotected to give xi by standard methods. ##STR7##
[0243] Isoxazoles of formula x wherein R is a masking group may be
prepared in this manner and the masking group transformed into
(R.sup.1).sub.m--P subsequent to isoxazole ring formation. For
example, the use of trialkylstannylacetylenes would result in a
trialkylstannyl isoxazole which may undergo reactions such as for
example Stille type cross coupling to introduce aryl substituents
by coupling to an appropriate aryl halide.
Synthesis of [1,2,4]-Oxadiazoles
[0244] ##STR8##
[0245] Carboxylic acids of formula iii may be used in the
preparation of the corresponding 3-R substituted [1,2,4]oxadiazoles
of formula xii by activation of the acid moiety, addition of a
suitable R-substituted hydroxyamidine to form an ester, followed by
cyclization to the oxadiazole. [See Tetrahedron Lett., 2001, 42,
1495-98, Tetrahedron Lett., 2001, 42, 1441-43, and Bioorg. Med.
Chem. Lett. 1999, 9, 1869-74]. The acid may be activated as the
mixed anhydride using an alkyl chloroformate such as isobutyl
chloroformate, in the presence of a base such as triethylamine in a
suitable solvent such as THF. Alternatively, other well known
methods of activating the acid may be employed, including in situ
activation of the acid using a reagent such as EDCI, DCC, DIC or
HBTU, with or without the presence of co-reagents such as HOBt or
DMAP, in suitable solvents such as DMF, DCM, THF, or MeCN at a
temperature from -20 to 100.degree. C. The cyclization may be
accomplished by heating in a solvent such as pyridine or DMF, under
microwave irradiation or by employing catalysts such as TBAF.
R-substituted hydroxyamidines are available from nitrites by
addition of hydroxylamine hydrochloride in the presence of a base
such as NaOH, NaHCO.sub.3 or Na.sub.2CO.sub.3, to generate the free
hydroxylamine, in a solvent such as ethanol or methanol or the
like, at temperatures between room temperature and 100.degree. C.
##STR9##
[0246] Compounds of formula ii wherein X is N-G.sup.2 provides a
convenient method of obtaining the free NH compound of formula I.
For example, the commercially available acid derivative of formula
iia wherein X is N-Boc may be orthogonally N-protected with a
protecting group G.sup.1 such as for example Fmoc. The resulting
intermediate iiia may be transformed into the corresponding
[1,2,4]-oxadiazoles using methods described above. When Fmoc is
employed for one of the protecting groups, [1,2,4]-oxadiazole ring
formation methods involving a base, such as activation with
chloroformate in the presence of triethylamine or ring closure in
pyridine, may effect removal of the protecting group giving xiiia
directly without isolation of the
2-(3-R-[1,2,4]oxadiazol-5-yl)-piperazine intermediate.
##STR10##
[0247] 5-R substituted [1,2,4]oxadiazoles of formula xiib may be
prepared from nitriles of formula vii by effectively reversing the
substituents attached to the [1,2,4]-oxadiazole. Nitriles of
formula vii react with hydroxylamine as described above to provide
the intermediate hydroxyamidine, and may be converted to the
[1,2,4]oxadiazoles of formula xiib using an acylating agent
containing the R group using the method described above for
conversion of compounds of formula iii to compounds of formula xii.
Synthesis of Tetrazoles ##STR11##
[0248] Nitriles of formula vii may be used in the preparation of
the corresponding tetrazoles of formula xviii by treatment with an
azide, such as NaN.sub.3, LiN.sub.3, trialkylyltinazide or
trimethylsilylazide, preferably with a catalyst such as dibutyltin
oxide or ZnBr.sub.2, in solvents such as DMF, water or toluene at a
temperature of 80 to 200.degree. C. by conventional heating or
microwave irradiation [See J. Org. Chem. 2001, 7945-7950; J. Org.
Chem. 2000, 7984-7989 or J. Org. Chem. 1993, 4139-4141].
[0249] N2-arylation of 5-substituted tetrazoles have been reported
in the literature using a variety of coupling partners. Compounds
of formula xviii wherein R is an aryl group may be prepared using
for example boronic acids of formula xv [with the B(OH).sub.2
moiety], or the corresponding iodonium salts of formula xvii [with
the I.sup.+--Ar moiety], or the corresponding triarylbismuth
diacetates [with the Bi(OAc).sub.2Ar.sub.2 moiety], as arylating
agents mediated by transition metals [See Tetrahedron Lett. 2002,
6221-6223; Tetrahedron Lett. 1998, 2941-2944; Tetrahedron Lett.
1999, 2747-2748]. With boronic acids, stoichiometric amounts of
Cu(II)acetate and pyridine are used in solvents such as
dichloromethane, DMF, dioxane or THF at a temperature of room
temperature to 100.degree. C. With iodonium salts, catalytic
amounts of Pd(II)-compounds, such as Pd(dba).sub.2 or
Pd(OAc).sub.2, together with catalytic amounts of
Cu(II)-carboxylates, such as Cu(II)-phenylcyclopropylcarboxylate,
and bidentate ligands, such as BINAP or DPPF, are used in solvents
such as t-BuOH at a temperature of 50 to 100.degree. C. With
triarylbismuth diacetates, catalytic amounts of cupric acetate may
be employed in the presence of N,N,N',N'-tetramethylguanidine in a
suitable solvent such as THF with heating at a temperature of
40-60.degree. C. Iodonium salts of formula xvi may be obtained
from, for example, the respective boronic acids by treatment with
hypervalent iodine substituted aromatics, such as
hydroxyl(tosyloxy)iodobenzene or PhI(OAc).sub.2x2TfOH, in
dichloromethane or the like [See Tetrahedron Lett. 2000,
5393-5396]. Triarylbismuth diacetates may be prepared from aryl
magnesium bromides with bismuth trichloride in a suitable solvent
such as refluxing THF to give the triarylbismuthane, which is then
oxidized to the diacetate using an oxidizing agent such as sodium
perborate in acetic acid [Synth. Commun. 1996, 4569-75].
Synthesis of [1,2,3]triazoles
[0250] ##STR12##
[0251] Ketoaldehydes of formula xix are available from compounds of
formula ii via activation of the acid moiety, reaction with
diazomethane to form an intermediate alpha-diazoketone, and
trapping with an acid such as acetic acid to form an
alpha-acetylated ketone intermediate, which can be converted to
compounds of formula xix by hydrolysis and oxidation. [See Bioorg.
Med. Chem. 2002, 10, 2199-2206] Ketoaldehydes of formula xix will
react with arylhydrazines with in acetic acid and water at -20 to
120.degree. C. to form bis-hydrazones of formula xx, which may
undergo cyclization in the presence of copper (II) sulfate in
aqueous mixtures of for example dioxane or THF at -20 to
120.degree. C. to form [1,2,3]triazoles of formula xxi. [See J.
Med. Chem. 1978, 21, 1254-60 and J. Org Chem. 1948, 13, 807-14]
Compounds of formula xxi may be deprotected as above to yield the
secondary amines of formula xxii. Synthesis of Q Ring:
Amino-Triazoles ##STR13##
[0252] The deprotected amines of formula xi, xiii, xviii and xxii
may be subjected to a sequence of thiourea formation, methylation
and triazole formation to deliver compounds of formula I wherein
the Q ring is a triazole attached to the newly deprotected
secondary amine. Thioureas of formula xxiv are available from well
established methods using for example an isothiocyanate,
R.sup.2SCN, or 1,1-thiocarbonyl-diimidazole in the presence of
R.sup.2NH.sub.2, in a solvent such as methanol, ethanol and the
like, at a temperature between room temperature and 100.degree. C.,
and are typically carried out at 60.degree. C. Alkylation of the
thiourea intermediates can be performed using an alkylating agents
such iodomethane or iodoethane, in a solvent such as DMF, acetone,
CH.sub.2Cl.sub.2, at room temperature or elevated temperatures to
give the isothiourea of formula xxv. When an iodoalkane is
employed, the product may be isolated as the hydroiodide salt [See
Synth. Commun. 1998, 28, 741-746]. Compounds of formula xxv may
react with an acyl hydrazine or with hydrazine followed by an
acylating agent to form an intermediate which may be cyclized to
the 3-aminotriazoles of formula xxvi by heating at 50 to
200.degree. C. in a suitable solvent such as pyridine or DMF. Other
Functional Group Transformations ##STR14##
[0253] It is to be understood that when additional functional
groups are present in compounds of formula I or any precursor,
those functional groups may be employed to introduce other
substituents or functional groups by methods established in the art
when there are no other incompatible reactive sites. For example,
in compounds of formula xxvii available from the orthogonally
protected bisamine xiiia described above, the secondary amine
obtained by deprotection of G.sup.2 may undergo alkylation or
reductive amination to generate a tertiary amine of formula xix.
Additionally, other substituents not explicitly drawn in the
schemes may be present as described in formula I providing no
interference with the reactions described above is caused by said
substituents.
[0254] The invention further relates to the following compounds,
which may be used as intermediates in the preparation of compounds
of formula I; [0255] Methyl 4-dimethylaminomethyl-benzoate [0256]
Ethyl 4-(2-dimethylamino-ethoxy)-benzoate [0257]
4-Dimethylaminomethyl-benzoic acid hydrazide [0258]
4-(2-Dimethylamino-ethoxy)-benzoic acid hydrazide [0259]
4-Difluoromethoxy-benzoic acid hydrazide [0260]
Tris-(3-chloro-phenyl)-bismuthane [0261]
Tris-(3-chloro-phenyl)-bismuthane diacetate [0262]
2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester
[0263] Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester [0264]
piperazine-1,2,4-tricarboxylic acid 4-tert-butyl ester
1-(9H-fluoren-9-ylmethyl) ester [0265]
2-Formyl-piperidine-1-carboxylic acid tert-butyl ester [0266]
Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester
[0267] 3-Formyl-morpholine-4-carboxylic acid tert-butyl ester
[0268] 2-Cyano-piperidine-1-carboxylic acid tert-butyl ester [0269]
2-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester
[0270] 2-(Hydroxyimino-methyl)-piperidine-1-carboxylic acid
tert-butyl ester [0271]
3-(Hydroxyimino-methyl)-morpholine-4-carboxylic acid tert-butyl
ester [0272]
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid
tert-butyl ester [0273]
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid
tert-butyl ester [0274]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic
acid tert-butyl ester [0275]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic
acid tert-butyl ester [0276]
2-[2-(3-chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carboxylic
acid tert-butyl ester [0277]
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine [0278]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-morpholine [0279]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine [0280]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine [0281]
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid
methylamide [0282]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioic acid
methylamide [0283]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carbothioic
acid methylamide [0284]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamoyl-piper-
azine-1-carboxylic acid tert-butyl ester [0285]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioic
acid methylamide [0286]
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-piperidine-1-carboximidoth-
ioic acid methyl ester [0287]
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboximidoth-
ioic acid methyl ester [0288]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-methylmorpholine-4-carboxim-
idothioic acid methyl ester [0289]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfan-
yl-methyl)-piperazine-1-carboxylic acid tert-butyl ester [0290]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboximid-
othioic acid methyl ester
EXAMPLES
[0291] The invention will now be illustrated by the following
non-limiting examples.
General Methods
[0292] All starting materials are commercially available or earlier
described in the literature. The .sup.1H and .sup.13C NMR spectra
were recorded either on Bruker 300, Bruker DPX400 or Varian +400
spectrometers operating at 300, 400 and 400 MHz for .sup.1H NMR
respectively, using TMS or the residual solvent signal as
reference, in deuterated chloroform as solvent unless otherwise
indicated. All reported chemical shifts are in ppm on the
delta-scale, and the fine splitting of the signals as appearing in
the recordings (s: singlet, br s: broad singlet, d: doublet, t:
triplet, q: quartet, m: multiplet).
[0293] Analytical in line liquid chromatography separations
followed by mass spectra detections, were recorded on a Waters LCMS
consisting of an Alliance 2795 (LC) and a ZQ single quadropole mass
spectrometer. The mass spectrometer was equipped with an
electrospray ion source operated in a positive and/or negative ion
mode. The ion spray voltage was +3 kV and the mass spectrometer was
scanned from m/z 100-700 at a scan time of 0.8 s. To the column,
X-Terra MS, Waters, C8, 2.1.times.50 mm, 3.5 mm, was applied a
linear gradient from 5% to 100% acetonitrile in 10 mM ammonium
acetate (aq.), or in 0.1% TFA (aq.). Preparative reversed phase
chromatography was run on a Gilson autopreparative HPLC with a
diode array detector using an XTerra MS C8, 19.times.300 mm, 7 mm
as column. Purification by a chromatotron was performed on rotating
silica gel/gypsum (Merck, 60 PF-254 with calcium sulphate) coated
glass sheets, with coating layer of 1, 2, or 4 mm using a TC
Research 7924T chromatotron. Purification of products were also
done by flash chromatography in silica-filled glass columns or in
plastic SPE tubes pre-filled with silica gel.
[0294] Microwave heating was performed in a Smith Synthesizer
Single-mode microwave cavity producing continuous irradiation at
2450 MHz (Personal Chemistry AB, Uppsala, Sweden).
Example 1
Methyl 4-dimethylaminomethyl-benzoate
[0295] Methyl 4-(bromomethyl)benzoate (4.58 g, 20 mmol) was mixed
with 45% dimethylamine (5.57 mL, 2.5 mmol) in THF (50 mL) at room
temperature for 30 min. The mixture was concentrated in vacuo and
the residue was diluted with water and extracted with ether. The
organic layer was dried with MgSO.sub.4 and concentrated in vacuo
to give the title compound (4.0 g) as pale yellow oil. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.01 (d, 2H), 7.40 (d, 2H), 3.92 (s,
3H), 3.48 (s, 2H) and 2.26 (s, 6H).
Example 2
Ethyl 4-(2-dimethylamino-ethoxy)-benzoate
[0296] Ethyl 4-hydroxy-benzoate (16.6 g, 0.1 mol) was mixed with
(2-chloro-ethyl)-dimethyl-amine hydrochloride (40 g, 0.28 mol) and
K.sub.2CO.sub.3 (100 g, 0.724 mol) in DMF. The mixture was heated
to 150.degree. C. for 4 h, and then poured into ice-water and the
product was extracted into ethyl acetate. The ethyl acetate layer
was washed with brine and the product was acidified with 1N HCl
(130 mL) and the ethyl acetate layer was discarded. The acidified
aqueous layer was washed with ethyl acetate, then basified with 2M
sodium carbonate (100 mL) and the product was extracted into ethyl
acetate again. This organic layer was washed with brine, dried with
MgSO.sub.4, filtered and concentrated to give the title compound
(12.6 g, 53%) as a sticky pale yellow-brown oil. .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.01 (d, 2H), 6.95 (d, 2H), 4.36 (q,
2H), 4.13 (t, 2H), 2.76 (t, 2H), 2.36 (s, 6H) and 1.39 (t, 3H).
Example 3
4-Dimethylaminomethyl-benzoic acid hydrazide
[0297] Methyl 4-dimethylaminomethyl-benzoate (4.0 g, 20 mmol) was
mixed with hydrazine hydrate (9.7 ml, 200 mmol) in methanol at
80.degree. C. overnight. The mixture was concentrated in vacuo and
the residue was triturated with ether to give the title compound
(3.37 g, 84.2%) as a white solid. .sup.1H NMR (DMSO-d.sub.6),
.delta. (ppm): 9.75 (w, 1H), 7.76 (d, 2H), 7.35 (d, 2H), 4.50 (w,
2H), 3.41 (s, 2H) and 2.13 (s, 6H).
Example 4
4-(2-Dimethylamino-ethoxy)-benzoic acid hydrazide
[0298] Ethyl 4-(2-dimethylamino-ethoxy)-benzoate (12.6 g, 53 mmol)
was mixed with hydrazine hydride (26.5 g, 0.5 mol) in ethanol at
100.degree. C. in a sealed flask overnight. The mixture was
concentrated and triturated with ether to give the title compound
(9.83 g, 82.9%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6),
.delta. (ppm): 9.62 (s, 1H), 7.77 (d, 2H), 6.97 (d, 2H), 4.45 (b,
2H), 4.08 (t, 2H), 2.61 (t, 2H) and 2.20 (s, 6H).
Example 5
4-Difluoromethoxy-benzoic acid hydrazide
[0299] HOBt (2.2 g, 15.9 mmol) and EDCI (3.1 g, 15.9 mmol) were
added to 4-difluoromethoxy-benzoic acid (2.5 g, 13.3 mmol) in
acetonitrile (25 mL) at room temperature. After two hours, a
solution of hydrazine monohydrate (0.493 mL, 10.2 mmol) and
cyclohexane (0.33 mL) in acetonitrile (5.0 mL) was added drop-wise
at 0.degree. C. After stirring at room temperature for 2 hours, the
solvent was removed in vacuo and the residue was diluted with ethyl
acetate, washed saturated sodium bicarbonate (4 times), dried over
sodium sulfate, filtered and concentrated to afford the title
compound (2.12 g, 79%, white solid). .sup.1H NMR (DMSO) .delta.
(ppm): 9.80 (bs, 1H), 7.88 (m, 2H), 7.34 (t, 1H), 7.23 (m, 2H),
4.50 (bs, 2H).
Example 6
Bis-(3-chloro-phenyl)-iodonium tetrafluoroborate
[0300] Bis(acetyloxy)(3-chlorophenyl)-.lamda.-3-iodane was prepared
as in literature [Kazmierczak, P.; Skulski, L., Synthesis 1998, 12,
1721-1723]. To stirred mixture of 3-chlorophenylboronic acid 0.821
g (5.25 mmol) and BF.sub.3.Et.sub.2O (0.78 g, 5.5 mmol) in
dichloromethane (50 mL) at 0.degree. C. was added a solution of
bis(acetyloxy)(3-chlorophenyl)-.lamda.-3-iodane (1.78 g, 5 mmol) in
dichloromethane (50 mL) under argon, and the reaction mixture was
stirred for 1.5 hours at 0.degree. C. Saturated aqueous
NH.sub.4BF.sub.4 (10.5 g, 100 mol) was added and the reaction
mixture was stirred for an hour, poured into water and extracted
with dichloromethane. The organic layer was concentrated to give a
solid residue, which was triturated with diethyl ether to give the
title compound (off-white solid, 1.70 g, 78%). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.02 (m, 4H), 7.58 (dm, 2H), 7.4 (t,
2H).
Example 7
Copper(II) 2-phenylcyclopropanecarboxyate
[0301] Sodium hydroxide (0.81 g, 20.25 mmol) in water (10 mL) was
added to 2-phenylcyclopropanecarboxyate (32.4 g, 20 mmol) and the
mixture was stirred until the solid completely dissolved. A
solution of copper(II) sulfate (2.44 g, 10 mmol) in water was added
in a dropwise manner. The mixture was stirred for 2 h, and the pale
blue precipitate was collected by filtration, dried under vacuum
and used without further purification.
Example 8
2-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester
[0302] Di-tert-butyl dicarbonate (8.3 g, 38.2 mmol) was added to a
stirred solution of piperidinemethanol (4.0 g, 37.4 mmol) in
CH.sub.2Cl.sub.2 (50 mL) and 1N NaOH (50 mL, 50 mmol) was added.
The mixture was stirred at room temperature overnight. Reaction
mixture was diluted with CH.sub.2Cl.sub.2 and the aqueous phase was
separated. The aqueous phase was extracted with dichloromethane
(3.times.30 mL). The combined organic phase was washed with water
(30 mL) and brine (30 mL), dried (sodium sulfate), filtered and
concentrated in-vacuo to give the crude product which was
triturated with hexane to afford the title compound as white solid
(4.8 g, 64%).
Example 9
Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester
[0303] Di-tert-butyl dicarbonate (3.33 g, 15.3 mmol) was added to a
solution of morpholine-3-carboxylic acid (1.7 g, 10.2 mmol),
potassium carbonate (7.04 g, 51 mmol) in acetone (5 mL) and water
(10 mL) at 0.degree. C. The resulting mixture was stirred at room
temperature for 24 h, diluted with water (50 mL) and extracted with
diethyl ether (2.times.50 mL). The aqueous phase was treated with
hydrochloric acid (2M aqueous, 100 mL), extracted with
dichloromethane (2.times.50 mL). The combined organic phase was
washed with water (50 mL), brine (50 mL), dried (sodium sulfate),
filtered and concentrated in-vacuo to isolate the desired product
as white solid (1.98 g, 84%). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 4.46 (m, 2H), 3.80 (m, 3H), 3.53 (m, 1H), 3.31 (m, 1H), 1.48
(d, 9H).
Example 10
Piperazine-1,2,4-tricarboxylic acid 4-tert-butyl ester
1-(9H-fluoren-9-ylmethyl) ester
[0304] A solution of 9-fluorenylmethyl chloroformate (2.72 g, 10.5
mmol) in 1,4-dioxane (19 mL) was added drop-wise to a solution of
piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (2.20 g, 9.6
mmol) and N,N-diisopropylethylamine (4.2 mL, 23.9 mmol) in water
(9.5 mL) in an ice-bath. After stirring overnight at room
temperature, the reaction mixture was diluted with water and
extracted with chloroform (4 times). The organic layer was washed
with saturated sodium bicarbonate and water and then 1N HCl and
water, dried over anhydrous sodium sulfate, filtered, and
concentrated to afford piperazine-1,2,4-tricarboxylic acid
4-tert-butyl ester 1-(9H-fluoren-9-ylmethyl) ester (4.3 g).
Example 11
2-Formyl-piperidine-1-carboxylic acid tert-butyl ester
[0305] DMSO (7.14 mL, 98 mmol) was added drop-wise to a stirred
solution of oxalyl chloride (30 mL, 2M in CH.sub.2Cl.sub.2, 60
mmol) in CH.sub.2Cl.sub.2 (60 mL) at -78.degree. C. After 5
minutes, a solution of 2-hydroxymethyl-piperidine-1-carboxylic acid
tert-butyl ester in CH.sub.2Cl.sub.2 (25 mL) was added and the
reaction mixture as stirred at -78.degree. C. for 0.5 hours after
which Et.sub.3N (25 mL, 181 mmol) was and the mixture allowed to
warm slowly to room temperature with stirring. The mixture was then
poured into water (100 mL) and the organic layer was separated. The
organic extract was then washed with NaHCO.sub.3 (saturated). The
aqueous phase was extracted with dichloromethane (3.times.30 mL).
The combined organic phase was washed with water (30 mL) and brine
(30 mL), dried (sodium sulfate), filtered and concentrated in
vacuo. Chromatography gave the title product as a yellow oil (3.27
g, 73%).
Example 12
Morpholine-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl
ester
[0306] Iodomethane (0.32 mL, 5.19 mmol) was added to a solution of
morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (1 g, 4.32
mmol) and potassium carbonate in DMF (15 mL). The resulting mixture
was stirred at room temperature for 4 h, diluted with diethyl ether
(100 mL), and successively washed with water (3.times.100 mL) and
brine (100 mL). The organic phase was dried (sodium sulfate),
filtered and concentrated in-vacuo to isolate the desired compound
as clear oil (0.99 g, 94%). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 4.40 (m, 2H), 3.75 (m, 6H), 3.39 (m, 2H), 1.46 (d, 9H).
Example 13
3-Formyl-morpholine-4-carboxylic acid tert-butyl ester
[0307] Diisobutylaluminum hydride (1M in toluene), was added
drop-wise to a solution of morpholine-3,4-dicarboxylic acid
4-tert-butyl ester 3-methyl ester (992 mg, 4.05 mmol) in toluene
(10 mL) at -78.degree. C., and left stirring at -78.degree. C. for
1 h. The reaction was quenched by slow addition of sodium sulfate
decahydrate (0.6 g) with stirring at 80.degree. C. for 40 minutes.
The mixture was filtered while hot through a celite pad using ethyl
acetate. The filtrate was concentrated in vacuo and chromatography
(silica gel, 8% acetone in hexanes) yielded the title product as a
white solid (539 mg, 62%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
9.68 (s, 1H), 4.45 (m, 2H), 3.86 (m, 2H), 3.70 (dd, 1H), 3.51 (m,
1H), 3.23 (m, 1H), 1.48 (m, 9H).
Example 14
a) 2-Cyano-piperidine-1-carboxylic acid tert-butyl ester
[0308] Piperidine-1,2-dicarboxylic acid-1-tert-butyl ester (12.8 g,
55.6 mmol) and THF (170 mL) were added to a 500 mL round bottom
flask equipped with stir bar. The solution was cooled to
-20.degree. C. and triethylamine (10.1 mL, 72.3 mmol) was added
followed by ethyl chloroformate (5.32 mL, 55.6 mmol). The resulting
white precipitate was left stirring at -10.degree. C. for 1 h.
Aqueous ammonia (22.6 mL, 1168 mmol) was added to the above
reaction mixture and the clear reaction mixture was stirred at room
temperature overnight. The reaction mixture was concentrated in
vacuo and the isolated residue was dissolved in ethyl acetate (300
mL). The organic phase was successively washed with water (300 mL)
and brine (200 mL), dried (sodium sulfate), filtered and
concentrated in vacuo to isolate a clear gum. The gum was
triturated with hexanes to isolate the carbamate (9.4 g, 74%) as a
white solid. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 6.03 (bs,
1H), 5.55 (bs, 1H), 4.77 (bs, 1H), 4.05 (bs, 1H), 2.81 (t, 1H),
2.27 (bs, 1H), 1.47 (m, 14H).
[0309] Acetonitrile (220 mL) and DMF (3.82 mL, 49.4 mmol) were
added to a 500 mL round bottom flask equipped with stir bar. Cooled
the mixture down to -5.degree. C. and to it added oxalyl chloride
(24.7 mL, 49.4 mmol, 2 M dichloromethane). The resulting mixture
was stirred for 15 min. This was followed by addition of solution
of 2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (9.4
g, 41.2 mmol) in acetonitrile (50 mL) and pyridine (8.3 mL, 103
mmol). Reaction mixture was left stirring at room temperature
overnight. The reaction mixture was concentrated in vacuo and the
residue was dissolved in ethyl acetate (300 mL). The organic phase
was successively washed with water (300 mL) and brine (200 mL),
dried (sodium sulfate), filtered and concentrated in vacuo to
isolate the title compound (8.44 g, 97%) as a yellow solid. .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 5.23 (bs, 1H), 4.03 (bs, 1H), 2.93
(t, 1H), 1.75 (m, 5H), 1.46 (m, 10H).
b) tert-Butyl 3-cyanomorpholine-4-carboxylate
[0310] Triethylamine (1.808 mL, 12.97 mmol) and ethyl chloroformate
(0.909 mL, 9.514 mmol) were added to a cooled (0.degree. C.)
solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester
(2.00 g, 8.65 mmol) in THF (25 mL). The reaction was warmed to room
temperature and allowed to stir for 2 h, then cooled to 0.degree.
C. and ammonium hydroxide (4 mL) was added. The resulting mixture
was warmed to room temperature and stirred for a further 1 h. The
solvent was removed in vacuo, and the product was extracted from
the aqueous phase with dichloromethane. The combined organics were
dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure to yield 3-carbamoyl-morpholine-4-carboxylic acid
tert-butyl ester (off-white solid, 1.37 g, 69%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta.=1.51 (s, 9H); 3.19 (m, 1H); 3.52 (m, 2H);
3.88 (m, 2H); 4.50 (d, J=11.4, 1H); 5.81 (s broad, 1H); 6.05 (s
broad, 1H).
[0311] Oxalyl chloride (3.87 mL of 2M in DCM, 7.73 mmol) was added
to a cooled (0.degree. C.) solution of dimethylformamide (0.598 mL,
7.73 mmol) in acetonitrile (15 mL). The solution was stirred for 20
min at 0.degree. C. A solution of
3-carbamoyl-morpholine-4-carboxylic acid tert-butyl ester (1.37 g,
5.95 mmol) in acetonitrile (6 mL) and pyridine (0.481 mL, 5.95
mmol) was added to the first solution. The mixture was allowed to
warm to room temperature and stirred for 30 min. The solvent was
removed in vacuo, and the resulting residue was dissolved in
dichloromethane and washed with water. The aqueous phase was
re-extracted with dichloromethane. The combined organics were dried
(Na.sub.2SO.sub.4-), filtered and concentrated under reduced
pressure to yield the title compound (off white crystals, 1.24 g,
98%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=1.51 (s, 9H); 3.26
(m, 1H); 3.55 (td, J=11.8 Hz, 2.7 Hz, 1H); 3.41 (dd, J=11.8 Hz, 3.3
Hz, 1H); 3.83 (m, 1H); 3.98 (d, J=11.4 Hz, 1H); 4.08 (d, J=12 Hz,
1H); 5.32 (m, 1H).
Example 15
a) tert-butyl 2-(2H-tetrazol-5-yl)piperidine-1-carboxylate
[0312] tert-Butyl 2-cyanopiperidine-1-carboxylate (2.10 g, 10 mmol)
was mixed with sodium azide (0.715 g, 11 mmol) and ammonium
chloride (0.588 g, 11 mmol) in DMF (7.5 mL) and heated at
100.degree. C. overnight. The reaction mixture was quenched with
water and extracted with ethyl acetate. The organic layer was
washed with water three times and then with brine, dried and
concentrated to give the title compound (white solid, 2.34 g,
92.5%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 5.7 (m, 1H), 4.02
(m, 1H), 2.93 (m, 1H), 2.35 (m, 1H), 2.07 (m, 1H), 1.74 (m, 3H),
1.49 (m+s, 11H).
[0313] The following compound was made in the same manner:
b) tert-Butyl 3-(2H-tetrazol-5-yl)morpholine-4-carboxylate
[0314] tert-Butyl 3-cyanomorpholine-4-carboxylate (2.74 g, 12.9
mmol) was mixed with sodium azide (0.923 g, 14.2 mmol) and ammonium
chloride (0.759 g, 14.2 mmol) in DMF (8 mL) and heated at
100.degree. C. for 6 h and left stirring at room temperature
overnight. The reaction mixture was quenched with water, acidified
to pH 3, and extracted with ethyl acetate. The organic layer was
washed with water three times and then with brine, dried and
concentrated to give the title compound (white solid, 2.64 g,
80.7%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 5.5 (br s, 1H),
4.45 (d, 1H), 3.8-3.98 (m, 3H), 3.62 (t, 1H), 3.3 (br s, 1H), 1.46
(s, 9H).
Example 16
2-(Hydroxyimino-methyl)-piperidine-1-carboxylic acid tert-butyl
ester
[0315] 2-Formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0
g, 4.7 mmol) in pyridine (1.3 mL) was added to a solution of
hydroxylamine hydrochloride (407 mg, 5.9 mmol) in pyridine (5.0 mL)
at 0.degree. C., and the mixture was stirred at room temperature
for 12 h. The mixture was diluted with water (50 mL), extracted
with dichloromethane (3.times.25 mL). The combined organic phase
was washed with brine (50 mL), dried (sodium sulfate), filtered and
concentrated in vacuo to isolate the desired compound as light
yellow oil (1.0 g).
Example 17
3-(Hydroxyimino-methyl)-morpholine-4-carboxylic acid tert-butyl
ester
[0316] A solution of 3-formyl-morpholine-4-carboxylic acid
tert-butyl ester (539 mg, 2.50 mmol) in pyridine (1.3 mL) was added
to a solution of hydroxylamine hydrochloride (217 mg, 3.13 mmol) in
pyridine (2.5 mL) at 0.degree. C. The mixture was warmed to room
temperature and stirred for 12 h, diluted with water (50 mL), and
extracted with dichloromethane (3.times.25 mL). The combined
organic phase was washed with brine (50 mL), dried (sodium
sulfate), filtered and concentrated, in-vacuo to isolate the
desired compound as light yellow oil (578 mg).
Example 18
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid
tert-butyl ester
[0317] N-chlorosuccinimide (643 mg, 4.82) in DMF (6 mL) was added
to 2-(hydroxyimino-methyl)-piperidine-1-carboxylic acid tert-butyl
ester (1.0 g, 4.38 mmol) in dimethylformamide (10 mL) at 40.degree.
C. The mixture was stirred at 40.degree. C. for 1.5 h, cooled to
room temperature, diluted with diethyl ether (75 mL), and
sequentially washed with water (3.times.100 mL) and brine (100 mL).
The organic phase was dried (sodium sulfate), filtered and
concentrated in vacuo, to give the intermediate as a yellow
oil.
[0318] The intermediate in dichloromethane (5 mL) was added to
3-chloro-1-ethynylbenzene (1.24 mL, 10 mmol) and triethylamine
(1.05 mL, 7.54 mmol) and dichloromethane (5 mL) at 0.degree. C. and
the mixture was stirred at room temperature for 12 h, and
concentrated in vacuo. The residue was dissolved in ethyl acetate
(75 mL), and sequentially washed with water (3.times.50 mL) and
brine (50 mL). The organic phase was dried (sodium sulfate),
filtered and concentrated in vacuo. Chromatography (silica gel, 2%
ethyl acetate in dichloromethane) gave the title compound as a
yellow solid (236 mg). .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
7.75 (dd, 1H), 7.64 (m, 1H), 7.40 (m, 2H), 6.37 (s, 1H), 5.48 (br,
1H), 4.08 (m, 1H), 2.83 (m, 1H), 2.35 (m, 1H), 2.00-1.53 (m, 5H),
1.52 (s, 9H).
Example 19
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid
tert-butyl ester
[0319] A solution of N-chlorosuccinimide in dimethylformamide (6
mL) was added to a solution of
3-(hydroxyimino-methyl)-morpholine-4-carboxylic acid tert-butyl
ester (578 mg, 2.51 mmol) in dimethylformamide (10 mL) at
40.degree. C., and the mixture was stirred at 40.degree. C. for 1.5
h. The reaction mixture was cooled to room temperature, diluted
with diethyl ether (75 mL), sequentially washed with water
(3.times.100 mL) and brine (100 mL). The organic phase was dried
(sodium sulfate), filtered and concentrated, in-vacuo, to isolate
the intermediate as clear oil.
[0320] The intermediate in dichloromethane (5 mL) was added to a
solution of 3-chloro-1-ethynylbenzene (1.24 mL, 10 mmol),
triethylamine (1.05 mL, 7.54 mmol) in dichloromethane (5 mL) at
0.degree. C. and the mixture was stirred at room temperature for 12
h. The reaction mixture was concentrated in vacuo, dissolved in
ethyl acetate (75 mL), and sequentially washed with water
(3.times.50 mL) and brine (50 mL). The organic phase was dried
(sodium sulfate), filtered and concentrated, in-vacuo.
Chromatography (silica gel, 2% ethyl acetate in dichloromethane)
yielded the title compound as a yellow solid (236 mg). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.76 (bs, 1H), 7.67 (m, 1H), 7.43 (m,
2H), 6.51 (s, 1H), 5.24 (m, 1H), 4.39 (d, 1H), 3.88 (m, 3H), 3.60
(dt, 1H), 3.24 (m, 1H), 1.52 (s, 9H).
Example 20
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic
acid tert-butyl ester
[0321] Isobutyl chloroformate (0.42 mL, 3.24 mmol) was added to a
solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester
(500 mg, 2.16 mmol) and triethylamine (0.805 mL, 5.79 mmol) in THF
(15 mL) at 0.degree. C. The mixture was warmed to room temperature
for 2 hours. 3-Chloro-N-hydroxy-benzamidine was added (368 mg, 2.16
mmol) and the mixture was stirred overnight at room temperature,
then cooled and diluted with ethyl acetate (350 mL). The organic
layer was washed with water (2.times.30 mL) and brine (30 mL),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. Chromatography (silica gel, 30-40% ethyl acetate in hexanes)
yielded the ester (755 mg, 91%). .sup.1H NMR (CDCl.sub.3), .delta.
(ppm): 7.73 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.38 (dd, 1H),
5.25 (d, 2H), 4.4-4.8 (m, 2H), 4.1-3.2 (m, 5H), 1.50 (s, 9H).
[0322] A solution of the ester in DMF was heated at 127.degree. C.
for 2 hours. The product was extracted into ethyl acetate (100 mL)
and the organic layer was washed with water (3.times.20 mL) and
brine (20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The title compound (783 mg) was obtained in
quantitative yield. .sup.1H NMR (CDCl.sub.3): 8.09 (s, 1H), 7.98
(d, 1H), 7.46 (m, 2H), 4.50 (s, 1H), 4.2-3.2 (m, 6H), 1.49 (s,
9H).
Example 21
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic
acid tert-butyl ester
[0323] Piperazine-1,2,4-tricarboxylic acid 4-tert-butyl ester
1-(9H-fluoren-9-ylmethyl) ester (4.3 g, 9.6 mmol),
3-chloro-N-hydroxy-benzamidine (1.8 g, 10.5 mmol), HOBt (1.4 g,
10.5 mmol) and EDCI (2.0 g, 10.5 mmol) in DMF (25 mL) were stirred
at room temperature overnight. The reaction mixture was diluted
with ethyl acetate, washed with water (3 times), saturated sodium
bicarbonate and brine, dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was dissolved in DMF (20 mL)
and then heated at 135.degree. C. for 2 hours. After cooling, the
reaction mixture was diluted with ethyl acetate, washed with water
(3 times) and brine, dried over anhydrous sodium sulfate, filtered
and concentrated. Chromatography (silica gel, hexanes to 1:1
hexanes:dichloromethane to 1:3:4 ethyl
acetate:hexanes:dichloromethane to 3:1:4 ethyl
acetate:hexanes:dichloromethane) afforded the title compound (1.35
g, 39%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.12 (m, 1H), 8.00
(m, 1H), 7.47 (m, 2H), 4.21 (m, 2H), 3.81 (m, 1H), 3.25 (m, 2H),
2.81 (m, 2H), 2.38 (bs, 1H), 1.50 (bs, 9H).
Example 22
a) tert-Butyl
2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-carboxylate
[0324] A mixture of tert-butyl
2-(2H-tetrazol-5-yl)piperidine-1-carboxylate (253 mg, 1 mmol),
sodium t-butoxide (96 mg, 1 mmol), rac-BINAP (24.9 mg, 0.04 mmol),
Pd.sub.2(dba).sub.3 (10.4 mg, 0.01 mmol), copper(II)
2-phenylcyclopropanecarboxyate (7.72 mg, 0.02 mmol) and
bis-(3-chloro-phenyl)-iodonium tetrafluoroborate (436.8 mg, 1 mmol)
was refluxed in t-butanol (20 mL) under argon for two hours. After
the solvent was removed in vacuo, chromatography (5% ethyl acetate
in hexanes) gave the title compound (pale-yellow sticky oil, 237.8
mg, 65.3%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.14 (d, 1H),
8.03 (dm, 1H), 7.46 (m, 2H), 5.75 (br s, 1H), 4.1 (m, 1H), 3.05 (m,
1H), 2.43 (d, 1H), 1.99 (tm, 1H), 1.7 (t, 2H), 1.53 (m+s, 11H).
[0325] The following compound was made in the same manner:
b) tert-Butyl
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]morpholine-4-carboxylate
[0326] A mixture of tert-Butyl
3-(2H-tetrazol-5-yl)morpholine-4-carboxylate (701 mg, 2.74 mmol),
sodium t-butoxide (264 mg, 2.74 mmol), rac-BINAP (68.5 mg, 0.11
mmol), Pd.sub.2(dba).sub.3 (28.4 mg, 0.0274 mmol), copper(II)
(1R,2R)-2-phenylcyclopropanecarboxyate (21.2 mg, 0.059 mmol) and
bis-(3-chloro-phenyl)-iodonium tetrafluoroborate (1200 mg, 2.74
mmol) was refluxed in t-butanol (40 mL) under argon for two hours.
After the solvent was removed in vacuo, chromatography (5-20% ethyl
acetate in hexanes) gave the title compound (colorless sticky oil,
840 mg, 83.7%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.14 (s,
1H), 8.03 (dm, 1H), 7.48 (m, 2H), 5.40 (br s, 1H), 4.56 (d, 1H),
3.94 (dd, 1H), 3.90 (m, 2H), 3.62 (td, 1H), 3.47 (br s, 1H).
Example 23
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine
[0327] Trifluoroacetic acid (5 mL) was added to
2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carboxylic acid
tert-butyl ester (500 mg, 1.38 mmol) in dichloromethane (5 mL) and
the mixture was stirred at room temperature for 1 h, concentrated
to dryness, and the residue was dissolved in sodium hydroxide (1N
aqueous, 30 mL). The aqueous phase was extracted with
dichloromethane (3.times.30 mL). The combined organic phase was
washed with water (30 mL) and brine (30 mL), dried (sodium
sulfate), filtered and concentrated in vacuo to give the title
compound as light yellow oil (292 mg, 81%). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.75 (dd, 1H), 7.65 (m, 1H), 7.41 (m,
2H), 6.60 (s, 1H), 3.94 (dd, 1H), 3.17 (m, 1H), 2.83 (m, 1H), 2.35
(m, 1H), 2.00-1.53 (m, 6H).
Example 24
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-morpholine
[0328] Trifluoroacetic acid (2 mL) was added to
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carboxylic acid
tert-butyl ester (236 mg, 0.65 mmol) in dichloromethane (2 mL). The
mixture was stirred at room temperature for 1 h, concentrated to
dryness, and the residue was dissolved in sodium hydroxide (1N
aqueous, 30 mL). The aqueous phase was extracted with
dichloromethane (3.times.30 mL). The combined organic phase was
washed with water (30 mL) and brine (30 mL), dried (sodium
sulfate), filtered and concentrated in vacuo to yield the title
compound as light yellow oil (171 mg, 99%). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 7.72 (s, 1H), 7.62 (m, 1H), 7.37 (m,
2H), 6.59 (s, 1H), 4.18 (dd, 1H), 4.00 (dd, 1H), 3.87 (dt, 1H),
3.62 (m, 2H), 3.03 (m, 2H), 2.10 (bs, 1H).
Example 25
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine
[0329] A solution of the
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carboxylic
acid tert-butyl ester (783 mg, 2.19 mmol) was dissolved in a
minimum amount of dichloromethane and then cooled to 0.degree. C.
in an ice bath. A 1:1 solution of trifluoroacetic acid:
dichloromethane (10 mL) was added and the mixture stirred at
0.degree. C. for 15 minutes, and the mixture was warmed to RT for
45 minutes. Ice cold water (20 mL) was added and the mixture was
neutralized with saturated sodium bicarbonate. The product was
extracted into dichloromethane (2.times.25 mL) and washed with
brine (2.times.25 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo. Chromatography (silica gel)
yielded the title compound (429 mg, 74%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.11 (s, 1H), 8.00 (d, 1H), 7.47 (m, 2H), 3.6-4.4
(m, 6H), 3.0-3.3 (m, 2H).
Example 26
a) 2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine
[0330] tert-Butyl
2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine-1-carboxylate
(237 mg, 0.651 mmol) was mixed with trifluoroacetic acid (0.85 mL)
and dichloromethane (0.85 mL) at 0.degree. C. 0.5 hour. The mixture
was poured into saturated sodium carbonate and extracted with
dichloromethane. Chromatography (20-100% ethyl acetate in hexanes)
gave 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidine (white
solid, 113 mg, 65.8%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
8.16 (s, 1H), 8.03 (dm, 1H), 7.46 (m, 2H), 4.17 (dm, 1H), 3.21 (dm,
1H), 2.84 (tm, 1H), 2.18 (dm, 1H), 2.15 (m, 1H), 1.94 (m, 1H), 1.8
(m, 1H), 1.68 (m, 1H), 1.59 (m, 2H).
[0331] The following compound was made in the same manner:
b) 3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]morpholine
[0332] tert-Butyl
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]morpholine-4-carboxylate
(840 mg, 2.296 mmol) was mixed with trifluoroacetic acid (6 mL) and
dichloromethane (6 mL) at 0.degree. C. 1.5 hour. The mixture was
poured into saturated sodium carbonate and extracted with
dichloromethane, dried and concentrated to yield the title compound
(pale yellow sticky oil, 550 mg, 90%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.18 (s, 1H), 8.06 (dm, 1H), 7.52 (m, 2H), 4.45 (dd,
1H), 4.24 (dd, 1H), 3.92 (dt, 1H), 3.87 (dd, 1H), 3.72 (ddd, 1H),
3.14 (m, 2H), 2.11 (brs, 1H).
Example 27
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid
methylamide
[0333] Methyl isothiocyanate (63 mg, 0.86 mmol) was added to
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine (150 mg, 0.57
mmol) in CH.sub.2Cl.sub.2 (4 mL) and the resulting mixture was
stirred at room temperature for 12 h. The mixture was concentrated
in vacuo and the isolated residue was triturated with 50% diethyl
ether in hexanes to isolate the desired compound as off-white solid
(quantitative).
Example 28
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioic acid
methylamide
[0334] Methyl isothiocyanate (46.2 mg, 0.63 mmol) was added to
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine (145 mg, 0.55
mmol) in CHCl.sub.3 (4 mL) and the resulting mixture was stirred at
room temperature for 12 h. The mixture was concentrated in vacuo
and the isolated residue was triturated with 50% diethyl ether in
hexanes to isolate the title compound as off-white solid (181 mg,
97%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.78 (m, 1H), 7.67
(m, 1H), 7.45 (m, 2H), 6.75 (s, 1H), 6.28 (m, 1H), 5.80 (m, 1H),
4.57 (d, 1H), 4.29 (d, 1H), 4.09 (dd, 1H), 3.99 (dd, 1H), 3.75 (dt,
1H), 3.45 (dt, 1H), 3.23 (d, 3H).
Example 29
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine-4-carbothioic
acid methylamide
[0335] Methyl isothiocyanate (161 mg, 2.2 mmol) and Et.sub.3N (0.61
mg, 4.4 mmol) were added to a solution of
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine (294 mg,
1.1 mmol) in CH.sub.2Cl.sub.2 (4 mL) and the mixture was stirred at
room temperature for 12 h, and concentrated in vacuo.
Chromatography gave the title compound as viscous oil (313 mg,
84%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.06 (d, 1H), 7.96
(dd, 1H), 7.48 (dd, 1H), 7.45 (t, 1H), 6.88 (dd, 1H), 6.01 (br, m,
1H), 4.57 (d, 1H), 3.99 (m, 2H), 3.80 (m, 2H), 3.67 (ddd, 1H), 3.26
(d,3H).
Example 30
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamoyl-pipera-
zine-1-carboxylic acid tert-butyl ester
[0336] Methyl isothiocyanate (256 mg, 3.50 mmol) was added to a
solution of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperazine-1-carboxylic
acid tert-butyl ester (1.11 g, 3.04 mmol) in chloroform (17 mL) at
room temperature. After stirring overnight, the mixture was
concentrated and chromatography (silica gel, 1:3:4 ethyl
acetate:hexanes:dichloromethane to 1.5:2.5:4 ethyl
acetate:hexanes:dichloromethane) afforded the title compound (796
mg, 60%). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.05 (m, 1H),
7.95 (m, 1H), 7.45 (m, 2H), 6.01 (m, 1H), 4.68 (m, 1H), 4.22 (m,
1H), 3.80 (m, 2H), 3.51 (m, 1H), 3.25 (m, 3H), 3.07 (m, 1H), 1.30
(bs, 9H).
Example 31
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioic
acid methylamide
[0337]
2-({2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}methyl)p-
yridine (600 mg, 2.38 mmoles) was mixed with methyl isothiocyante
(250 mg, 3.41 mmol) in chloroform (10 mL) at room temperature
overnight. The reaction mixture was concentrated and triturated
with ether to give the title compound as a white solid (676 mg,
88%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.13 (s, 1H), 8.03
(m, 1H), 7.51 (m, 2H), 6.93 (w, 1H), 6.06 (w, 1H), 4.24 (m 1H),
3.34 (m, 1H), 3.23 (d, 3H), 2.46 (m, 1H), 2.11 (m, 1H), 1.60-1.95
(m, 4H).
Example 32
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-piperidine-1-carboximidothi-
oic acid methyl ester
[0338] Iodomethane (50 .mu.l, 0.80 mmol) was added to
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidine-1-carbothioic acid
methylamide (181 mg, 0.54 mmol) in methanol (4 mL) and the
resulting mixture was stirred at 75.degree. C. for 3 h. The mixture
was cooled to room temperature, diluted with saturated sodium
bicarbonate (aqueous, 30 mL), extracted with dichloromethane
(3.times.20 mL). The combined organic phase was washed with brine
(30 mL), dried (sodium sulfate), filtered and concentrated in vacuo
to yield the title compound as yellow oil (0.19 g, 100%). .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 7.73 (dd, 1H), 7.64 (m, 1H), 7.38
(m, 2H), 6.60 (s, 1H), 5.37 (m, 1H), 4.25 (m, 1H), 3.95 (m, 2H),
3.67 (m, 2H), 3.32 (m, 1H), 3.25 (s, 3H), 2.36 (s, 3H).
Example 33
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboximidothi-
oic acid methyl ester
[0339] Iodomethane (50 .mu.l, 0.80 mmol) was added to
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-morpholine-4-carbothioic acid
methylamide (181 mg, 0.54 mmol) in methanol (4 mL) and the
resulting mixture was stirred at 75.degree. C. for 3 h. The mixture
was cooled to room temperature, diluted with saturated sodium
bicarbonate (aqueous, 30 mL), extracted with dichloromethane
(3.times.20 mL). The combined organic phase was washed with brine
(30 mL), dried (sodium sulfate), filtered and concentrated in vacuo
to yield the title compound as yellow oil (0.19 g, 100%). .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 7.73 (dd, 1H), 7.64 (m, 1H), 7.38
(m, 2H), 6.60 (s, 1H), 5.37 (m, 1H), 4.25 (m, 1H), 3.95 (m, 2H),
3.67 (m, 2H), 3.32 (m, 1H), 3.25 (s, 3H), 2.36 (s, 3H).
Example 34
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-methylmorpholine-4-carboximi-
dothioic acid methyl ester
[0340] Iodomethane (212 mg, 1.5 mmol) was added to a solution of
3-[3-(3-chloro-phenyl)[1,2,4]oxadiazol-5-yl]-morpholine-4-carbothioic
acid methylamide (313 mg, 0.92 mmol) in methanol (10 mL) and the
mixture was stirred at 75.degree. C. for 3 h. The mixture was
cooled to room temperature, diluted with saturated sodium
bicarbonate (aqueous, 30 mL), extracted with dichloromethane
(3.times.20 mL). The combined organic phase was washed with brine
(30 mL), dried (sodium sulfate), filtered and concentrated in vacuo
to yield the title compound as a white solid (248 mg, 76%). .sup.1H
NMR (CDCl.sub.3), .delta. (ppm) 8.08 (d, 1H), 7.95 (dd, 1H), 7.47
(dd, 1H), 7.43 (t, 1H), 5.47 (dd, 1H), 4.36 (d, 1H), 3.40-4.00 (m,
5H), 3.21 (s, 3H), 2.36 (s,3H).
Example 35
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methylsulfany-
l-methyl)-piperazine-1-carboxylic acid tert-butyl ester
[0341]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methylthiocarbamoy-
l-piperazine-1-carboxylic acid tert-butyl ester (796 mg, 1.82 mmol)
and iodomethane (0.170 mL, 2.73 mmol) in methanol (11 mL) were
heated at 75.degree. C. in a sealed vial for 2 hours. After
cooling, the mixture was concentrated and then the residue was
dissolved with dichloromethane. The organic layer was washed with
saturated sodium bicarbonate, dried over anhydrous sodium sulfate,
filtered, and concentrated. Chromatography (silica gel, 25% ethyl
acetate in hexanes) afforded the title compound (632 mg, 77%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.08 (m, 1H), 7.97 (m, 1H),
7.44 (m, 2H), 5.51 (m, 1H), 4.49 (m, 1H), 4.01 (m, 2H), 3.49 (m,
2H), 3.20 (s, 3H), 3.15 (m, 1H), 2.37 (s, 3H), 1.38 (bs, 9H).
Example 36
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-carboximido-
thioic acid methyl ester
[0342]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidine-1-carbothioic
acid methylamide (676 mg, 2.0 mmol) was mixed with iodomethane (0.4
mL) in methanol (15 mL) in a sealed vial at 80.degree. C. for 2
hours. The reaction mixture was concentrated by rotavapor. The
residue was basified with saturated sodium bicarbonate and extrated
with dichloromethane. The organic layer was dried with MgSO.sub.4
to give the title compound as a sticky pale-yellow oil (700 mg,
100%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.15 (s, 1H), 8.04
(d, 1H), 7.48 (m, 2H), 5.75 (m, 1H), 3.22 (m, 1H), 3.22 (m,s, 4H),
2.04 (s,m, 4H), 2.10 (m, 1H), 1.69 (m, 4H).
Example 37
a)
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-piperidin-1-yl}-4-methyl-4H
[1,2,4]triazol-3-yl)-pyridine
[0343] Isonicotinic acid hydrazide (42.3 mg, 0.31 mmol) was added
to 2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]
N-methy-1-piperidine-1-carboximidothioic acid methyl ester (90 mg,
0.26 mmol) in ethanol (1.5 mL). The mixture was stirred at
75.degree. C. for 12 h, and then diluted with dichloromethane (8
mL). The organic phase was sequentially washed with water
(4.times.10 mL) and brine (10 mL), dried (sodium sulfate), filtered
and concentrated in vacuo. Chromatography (silica gel, 10% methanol
in ethyl acetate) gave a yellow oil that was triturated with 30%
hexanes in diethyl ether to yield the title compound as an
off-white solid (50 mg). .sup.1H NMR (CDCl.sub.3), .delta. (ppm):
8.72 (d, 2H), 7.69 (s, 1H), 7.59 (m, 3H), 7.36 (m, 2H), 6.54 (s,
1H), 4.79 (dd, 1H), 3.64 (s, 3H), 3.28 (m, 2H), 2.20 (m, 2H),
1.90-1.73 (m, 4H).
[0344] The following compounds were prepared in a similar
manner:
[0345] b)
3-[5-(3-Chlorophenyl)-[1,2,4]oxadioazol-3-yl]-4-(5-pyridin-4-yl-
-4H-[1,2,4]triazol-3-yl)-morpholine; yield 40.2 mg, 24%, yellow
powder; .sup.1H NMR CDCl.sub.3 (300 MHz): 3.37 (m, 1H); 3.59 (m,
1H); 3.75 (s, 3H); 3.97 (m, 1H); 4.08 (m, 2H); 4.32 (dd, J=11.7 Hz,
3.3 Hz, 1H); 5.00 (m, 1H); 7.45 (t, J=8 Hz, 7.56 (d, J=8 Hz, 1H);
7.62 (d, J=4.8 Hz, 2H); 7.94 (d, J=7.8 Hz, 1H); 8.04 (m, 1H); 8.75
(br. s, 2H)
[0346] Enantiomers were separated using a Chiralpak AD
4.6.times.250 mm column, eluting with iPrOH/0.05% Et.sub.2NH at a
flowrate of 1 mL/min, to yield 12.5 mg of enantiomer 1, Rt 7.39
min. and 12.7 mg of enantiomer 2, Rt 12.57 min.
[0347] c)
3-[5-(3-Chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin--
3-yl-4H-1,2,4-triazol-3-yl)morpholine; yield 63.5 mg, 27%, off
white solid; .sup.1H NMR CDCl.sub.3 (300 MHz): 9.07 (s, 1H) 8.71 (d
of d, 1H), 8.16 (d oft, 1H), 7.75 (d, 1H), 7.64 (m, 1H), 7.41 (m,
3H), 6.83 (s, 1H), 5.18 (t, 1H), 4.25 (d, 2H), 4.12 (m, 1H), 3.99
(m, 1H), 3.72 (m, 1H), 3.49 (m, 1H), 3.38 (m, 1H), 1.30 (m, 1H),
1.14 (m, 2H), 0.60 (m, 1H).
[0348] Enantiomers were separated using a Chiralpak AD
4.6.times.250 mm column, eluting with iPrOH at a flowrate of 1
mL/min, to yield enantiomer 1 as an off-white solid, 14.4 mg, Rt
5.9 min. and enantiomer 2 as an off-white solid, 16.7 mg, Rt 23.7
min.
[0349] d)
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-cyclopropyl-5-pyridin--
4-yl-4H-1,2,4-triazol-3-yl)morpholine; yield 103.4 mg, 43%, white
solid; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.75 (d, 2H), 7.76 (m,
3H), 7.64 (m, 1H), 7.41 (m, 2H), 6.83 (s, 1H), 5.19(t, 1H), 4.25(d,
2H), 4.13 (m, 1H), 3.99 (t of d, 1H), 3.73(t of d, 1H), 3.50 (m,
1H), 3.41(m, 1H), 1.28 (m, 1H), 1.15 (m, 2H), 0.62 (m, 1H).
[0350] e)
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-(4-methyl-5-pyridin-3-yl--
4H-1,2,4-triazol-3-yl)morpholine; yield 85.0 mg, 35%, white solid;
.sup.1H NMR CDCl.sub.3 (300 MHz): 8.90 (d, 1H), 8.72 (m, 1H), 8.05
(d oft, 1H), 7.73 (m, 1H), 7.61 (m, 1H), 7.41 (m, 3H), 6.67 (s,
1H), 4.82 (m, 1H), 4.25 (d of d, 1H), 4.08 (m, 3H), 3.67 (s, 3H),
3.48 (m, 1H), 3.40 (m, 1H).
[0351] f)
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(6-methoxy-pyridin-3-
-yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-morpholine; yield 73.2 mg,
29%, off white solid; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.40 (d,
1H), 7.88 (d of d, 1H), 7.69 (s, 1H), 7.59 (m, 1H), 7.38 (m, 2H),
6.84(d, 1H), 6.65(s, 1H), 4.79 (m, 1H), 4.20 (d of d, 1H), 4.04 (m,
3H), 3.98 (s, 3H), 3.61(s, 3H), 3.44 (m, 1H), 3.36 (m, 1H).
[0352] g)
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methoxypyri-
din-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 26.6 mg,
5.8%, yellow oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.31 (d, 1H),
8.04 (t, 1H), 7.95 (dt, 1H), 7.44 (m, 2H), 7.24 (d, 1H), 7.02 (s,
1H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.05 (m, 2H),
4.02(s, 3H), 3.73 (s, 3H), 3.7 (m, 1H), 3.34 (m, 1H).
[0353] h)
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(2-methylpyrid-
in-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 42.3 mg,
9.6%, yellow oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.64 (br, 1H),
8.02 (t, 1H), 7.94 (dt, 1H), 7.44 (m, 4H), 5.14 (dd, 1H), 4.38 (dd,
1H), 4.19 (dd, 1H), 4.03 (m, 2H), 3.74 (s, 3H), 3.7 (m, 1H), 3.38
(m, 1H), 2.66 (s, 3H).
[0354] i)
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-[5-(5-fluoropyrid-
in-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 285 mg,
63.9%, yellow oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.72 (s, 1H),
8.59 (d, 1H), 8.03 (t, 1H), 7.94 (dt, 1H), 7.82 (dq, 1H), 7.45 (m,
2H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.05 (m, 2H),
3.75 (s, 3H), 3.7 (m, 1H), 3.38 (m, 1H).
[0355] j)
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(5-fluoropyridin-3-yl)-
-4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 40 mg, 38%,
off-white solid; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.73 (s, 1H),
8.59 (d, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.41 (m,
2H), 6.68 (s, 1H), 4.83 (m, 1H), 4.25 (m, 1H), 4.08 (m, 3H), 3.71
(s, 3H), 3.45 (m, 2H)
[0356] k)
3-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyrid-
in-2-yl-4H-1,2,4-triazol-3-yl)morpholine; yield 68 mg, 14.3%,
yellow oil; 90% pure by NMR; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.64
(d, 1H), 8.22 (d, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.78 (td, 1H),
7.28 (m, 3H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.03 (m,
2H), 4.02(s, 3H), 3.66 (m, 1H), 3.34 (m, 1H).
[0357] l)
4-[5-(5-fluoropyridin-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-3-[-
3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]morpholine; yield 103 mg,
36.2%, clear oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.74 (s, 1H),
8.61 (d, 1H), 8.38 (t, 1H), 8.02 (dt, 1H), 7.84 (dq, 2H), 7.21 (t,
1H), 5.14 (dd, 1H), 4.38 (dd, 1H), 4.19 (dd, 1H), 4.03 (m, 2H),
3.75(s, 3H), 3.70 (m, 1H), 3.38 (m, 1H)
[0358] m)
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]-4-(4-methyl-5-pyridin-
-4-yl-4H-1,2,4-triazol-3-yl)morpholine; yield 99.6 mg, 37.3%, clear
oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.78 (dd, 2H), 8.38 (t, 1H),
8.02 (dt, 1H), 7.84 (dt, 1H), 7.63 (dd, 2H), 7.21 (t, 1H), 5.14
(dd, 1H), 4.38 (dd, 1H), 4.18 (m, 1H), 4.03 (m, 2H), 3.76 (s, 3H),
3.71 (m, 1H), 3.37 (m, 1H).
[0359] n)
3-[5-(3-chlorophenyl)isoxazol-3-yl]-4-[5-(2-methylpyridin-4-yl)-
.sub.4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 5.6 mg, 5%,
yellow oil; .sup.1H NMR CDCl.sub.3 (300 MHz): 8.64 (d, 1H), 7.72
(m, 1H), 7.5 (m, 1H), 7.41 (m, 1H), 7.38 (m, 3H), 6.66 (s, 1H),
4.81 (m, 1H), 4.24 (m, 1H), 4.09 (m, 3H), 3.68 (s, 3H), 3.52 (m,
2H), 2.63 (s, 3H)
Example 38
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-(4-methyl-5-pyridin-4-yl-4H-[1,2,4-
]triazol-3-yl)-morpholine
[0360] Isonicotinic acid hydrazide (56.1 mg, 0.41 mmol) was added
to
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboximidoth-
ioic acid methyl ester (96 mg, 0.27 mmol) in ethanol. The resulting
mixture was left stirring at 75.degree. C. for 12 h, and then
diluted with dichloromethane (8 mL). The organic phase was
sequentially washed with water (4.times.10 mL) and brine (10 mL),
dried (sodium sulfate), filtered and concentrated in vacuo.
Chromatography (silica gel, 10% methanol in ethyl acetate) gave a
yellow oil that was triturated with 30% hexanes in diethyl ether to
yield the title compound as an off-white solid (46 mg). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.76 (d, 2H), 7.72 (dd, 1H), 7.62 (m,
3H), 7.42 (m, 2H), 6.67 (s, 1H), 4.82 (dd, 1H), 4.25 (dd, 1H), 4.07
(m, 3H), 3.71 (s, 3H), 3.45 (m, 2H).
[0361] Enantiomers were separated using a Chiralpak AD
4.6.times.250 mm column, eluting with iPrOH at a flowrate of 1
mL/min, to yield enantiomer 1 as a white solid, 9 mg, Rt 5.6 min.
and enantiomer 2 as a white solid, 9 mg, Rt 9.9 min.
Example 39
3-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-4-[5-(4-difluoromethoxy-phenyl)-4-me-
thyl-4H-[1,2,4]triazol-3-yl]-morpholine
[0362] Pyridine (30 .mu.l) and 4-difluoromethoxy-benzoic acid
hydrazide (57.9 mg, 0.29 mmol) were added to a solution of
3-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-morpholine-4-carboximidoth-
ioic acid methyl ester (960 mg, 0.27 mmol) in ethanol. The mixture
was stirred at 75.degree. C. for 48 h, and then diluted with
dichloromethane (8 mL). The organic phase was sequentially washed
with water (4.times.10 mL) and brine (10 mL), dried (sodium
sulfate), filtered and concentrated in vacuo. Chromatography
(silica gel, 10% dichloromethane in ethyl acetate) yielded the
title compound as clear oil (18 mg). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 7.67 (m, 4H), 7.39 (m, 2H), 7.23 (d, 2H), 6.66 (s,
1H), 6.58 (t, 1H), 4.80 (dd, 1H), 4.25 (dd, 1H), 4.07 (m, 3H), 3.61
(s, 3H), 3.40 (m, 2H).
Example 40
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4-
H-[1,2,4]triazol-3-yl)-morpholine
[0363] Pyridine (30 .mu.l) and isonicotinic acid hydrazide (60 mg,
0.29 mmol) were added to
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-methylmorpholine-4-carboxim-
idothioic acid methyl ester (101 mg, 0.44 mmol) in ethanol, and the
mixture was stirred at 75.degree. C. for 48 h, and the mixture was
diluted with dichloromethane (8 mL). The organic phase was
sequentially washed with water (4.times.10 mL) and brine (10 mL),
dried (sodium sulfate), filtered and concentrated in vacuo.
Chromatography (silica gel, 10% dichloromethane in ethyl acetate)
yielded the title compound as clear oil (40 mg, 33%). .sup.1H NMR
(CDCl.sub.3), .delta. (ppm): 8.78 (d, 2H), 8.03 (d, 1H), 7.92 (dd,
1H), 7.63 (d, 2H), 7.46 (dd, 1H), 7.40 (t, 1H), 5.14 (dd, 1H), 4.35
(d, 1H), 4.14 (m, 3H), 3.75 (s, 3H), 3.73 (m,1H), 3.39 (m, 1H).
Example 41
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phen-
yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-morpholine
[0364]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-N-methyl-morpholine--
4-carboximidothioic acid methyl ester (100 mg, 0.28 mmol),
4-difluoromethoxy-benzoic acid hydrazide (60.2 mg, 0.30 mmol) and
pyridine (4 drops) in ethanol (10 mL) were heated at 75.degree. C.
for 24 hours. After cooling, the reaction mixture was diluted with
ethyl acetate and then washed with water (5 times) and brine, dried
over anhydrous sodium sulfate, filtered and concentrated.
Chromatography (silica gel, 1-2% methanol in dichloromethane)
afforded the title compound (99.5 mg, 73%). .sup.1H NMR
(CDCl.sub.3) .delta. (ppm): 8.03 (m, 1H), 7.93 (m, 1H), 7.67 (m,
2H), 7.46 (m, 1H), 7.42 (m, 1H), 7.25 (m, 2H), 6.59 (t, 1H), 5.13
(m, 1H), 4.37 (m,1H), 4.16 (m, 1H), 4.01 (m, 2H), 3.66 (m, 1H),
3.67 (s, 3H), 3.36 (m, 1H).
Example 42
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4-
H-[1,2,4]triazol-3-yl)-piperazine-1-carboxylic acid tert-butyl
ester
[0365]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methy-
lsulfanyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester
(211.6 mg, 0.47 mmol) and isonicotinic hydrazide (96.5 mg, 0.70
mmol) in ethanol (6 mL) were heated at 80.degree. C. for 24 hours.
After cooling, the mixture was diluted with ethyl acetate and
washed with water (5 times) and brine, dried over anhydrous sodium
sulfate, filtered and concentrated. Chromatography (silica gel,
0-5% 2M methanolic ammonia in 1:1 ethyl acetate: dichloromethane)
afforded the title compound (168.5 mg, 69%, colorless oil). .sup.1H
NMR (CDCl.sub.3) .delta. (ppm): 8.77 (m, 2H), 8.04 (s, 1H), 7.94
(m, 1H), 7.62 (m, 2H), 7.44 (m, 2H), 5.08 (m, 1H), 4.15 (m, 1H)
4.06 (m, 1H), 3.75 (m, 3H), 3.73 (s, 3H), 3.32 (m, 1H), 1.43 (bs,
9H).
Example 43
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl-4-
H-1,2,4]triazol-3-yl)-piperazine
[0366] Trifluoroacetic acid (1.5 mL) was added to a solution of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-piperazine-1-carboxylic acid tert-butyl
ester (164 mg, 0.31 mmol) in dichloromethane (3 mL) at 0.degree. C.
and stirred for 2.5 hours. After the mixture was concentrated, the
residue was diluted with dichloromethane and then washed with
saturated sodium bicarbonate, dried over anhydrous sodium sulfate,
filtered and concentrated to afford the title compound (109 mg,
83%, white foam solid). .sup.1H NMR (CDCl.sub.3) .delta. (ppm):
8.75 (m, 2H), 8.02 (m, 1H), 7.93 (m, 1H), 7.62 (m, 2H), 7.43 (m,
2H), 5.01 (m, 1H), 3.73 (s, 3H), 3.62 (m, 2H), 3.40 (m, 1H), 3.22
(m, 3H).
Example 44
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-1-(4-methyl-5-pyrid-
in-4-yl-4H-[1,2,4]triazol-3-yl)-piperazine
[0367] Formic acid (0.1 mL), formaldehyde (37 wt. % solution in
water, 0.1 mL) and sodium cyanoborohydride (1.0 M in THF, 0.1 mL)
were added to a solution of
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-(4-methyl-5-pyridin-4-yl--
4H-1,2,4]triazol-3-yl)-piperazine (50.3 mg, 0.12 mmol) in methanol
(0.8 mL) at room temperature. After stirring for 30 minutes, the
mixture was diluted with water and extracted with chloroform (4
times), dried over anhydrous sodium sulfate, filtered and
concentrated. Chromatography (silica gel, 1-5% 2M methanolic
ammonia in dichloromethane) afforded the title compound (90%).
.sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.77 (m, 2H), 8.03 (m, 1H),
7.93 (m, 1H), 7.63 (m, 2H), 7.42 (m, 2H), 5.21 (m, 1H), 3.74 (s,
3H), 3.70 (m, 1H), 3.43 (m, 1H), 3.09 (m, 2H), 2.70 (m, 2H), 2.41
(s, 3H).
Example 45
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phen-
yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine-1-carboxylic acid
tert-butyl ester
[0368]
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(methylimino-methy-
lsulfanyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester
(211.3 mg, 0.47 mmol), 4-difluoromethoxy-benzoic acid hydrazide
(99.2 mg, 0.49 mmol) and pyridine (8 drops) in ethanol were heated
at 75.degree. C. for three days. After cooling, the reaction
mixture was diluted with ethyl acetate and then washed with water
(5 times) and brine, dried over anhydrous sodium sulfate, filtered
and concentrated. Chromatography (silica gel, ethyl
acetate:hexanes:dichloromethane 3:1:4 to 100% ethyl acetate)
afforded the title compound.
Example 46
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phen-
yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine
[0369] Trifluoroacetic acid (1.5 mL) was added to a solution of
3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine-1-carboxylic acid
tert-butyl ester at 0.degree. C. and stirred for 2.5 hours. After
the mixture was concentrated, the residue was diluted with
dichloromethane and then washed with saturated sodium bicarbonate,
dried over anhydrous sodium sulfate filtered, and concentrated.
Chromatography (silica gel, 3-4% 2M methanolic ammonia in
dichloromethane) afforded the titled compound (white solid, 31%
yield over 2 steps). .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.05
(m, 1H), 7.95 (m, 1H), 7.69 (m, 2H), 7.47 (m, 1H), 7.42 (m, 1H),
7.26 (m, 2H), 6.59 (t, 1H), 5.01 (m, 1H), 3.63 (m, 5H), 3.39 (m,
1H), 3.20 (m, 3H).
Example 47
2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phen-
yl)-4-methyl-4H-[1,2,4]triazol-3-yl]-4-methyl-piperazine
[0370] Formic acid (0.1 mL), formaldehyde (37 wt. % in water, 0.1
mL) and sodium cyanoborohydride (1.0M in THF, 0.1 mL) were added to
a solution of
2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-[5-(4-difluoromethoxy-phe-
nyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-piperazine (27.3 mg, 0.056
mmol) in methanol (0.8 mL) at room temperature. After stirring for
30 minutes, the mixture was diluted with water and extracted with
chloroform (3 times), dried over anhydrous sodium sulfate, filtered
and concentrated. Chromatography (silica gel, 1-3% methanol in
dichloromethane) afforded the titled compound (57%). .sup.1H NMR
(CDCl.sub.3) .delta. (ppm): 8.03 (m, 1H), 7.93 (m, 1H), 7.68 (m,
2H), 7.46 (m, 1H), 7.42 (m, 1H), 7.25 (m, 2H), 6.59 (t, 1H), 5.20
(m, 1H), 3.68 (m,1H), 3.66 (s, 3H), 3.40 (m, 1H), 3.12 (m, 1H),
3.02 (m, 1H), 2.69 (m, 2H), 2.40 (s, 3H).
Example 48
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)phenyl]-4-
-methyl-4H-1,2,4-triazol-3-yl}piperidine
[0371]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (70 mg, 0.2 mmol) was mixed with
4-difluoromethoxy-benzoic acid hydrazide (40.4 mg, 0.2 mmol) in
ethanol at 80.degree. C. overnight. The reaction mixture was
diluted with water and extracted with dichloromethane. The
dichloromethane layer was dried and purified by chromatography
(ethyl acetate) to give the title compound (37 mg, 38%). .sup.1H
NMR (CDCl.sub.3), .delta. (ppm): 8.09 (s, 1H), 7.99 (m, 1H), 7.66
(d, 2H), 7.46 (m, 2H), 7.24 (d, 2H), 6.58 (t, 1H), 5.10 (m, 1H),
3.66 (s, 3H), 3.48 (m, 1H), 3.30 (m, 1H), 1.70-2.30 (m, 6H).
Example 49
4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H-1-
,2,4-triazol-3-yl)pyridine
[0372]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (70 mg, 0.2 mmol) was mixed with
isonicotinic acid hydrazide (33.2 mg, 0.2 mmol) in ethanol at
80.degree. C. overnight. The reaction mixture was diluted with
water and extracted with dichloromethane. The dichloromethane layer
was dried and purified by chromatography (ethyl acetate) to give
the title compound (34 mg, 40.3%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.74 (d, 2H), 8.07 (s, 1H), 7.96 (m, 1H), 7.61 (d,
2H), 7.45 (m, 2H), 5.11(m, 1H), 3.73 (s, 3H), 3.48 (m, 1H), 3.30
(m, 1H), 1.70-2.30 (m, 6H).
Example 50
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-[5-(4-methoxyphenyl)-4-methyl-4H-
-1,2,4-triazol-3-yl]piperidine
[0373]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (70 mg, 0.2 mmol) was mixed with
4-methoxy-benzoic acid hydrazide (33.2 mg, 0.2 mmol) in ethanol at
80.degree. C. overnight. The reaction mixture was diluted with
water and extracted with dichloromethane. The dichloromethane layer
was dried and purified by chromatography (ethyl acetate) to give
the title compound (20.2 mg, 22.4%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.09 (s, 1H), 7.98 (m, 1H), 7.57 (d, 2H), 7.45 (m,
2H), 7.99 (d, 2H), 5.10 (m, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 3.48
(m, 1H), 3.29 (m, 1H), 1.70-2.30 (m, 6H).
Example 51
[4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl-4H--
1,2,4-triazol-3-yl)phenyl]dimethylamine
[0374]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (70 mg, 0.2 mmol) was mixed with
4-methoxy-benzoic acid hydrazide (27.4 mg, 0.2 mmol) in ethanol at
80.degree. C. overnight. The reaction mixture was diluted with
water and extracted with dichloromethane. The dichloromethane layer
was dried and purified by chromatography (ethyl acetate) to give
the title compound (20.2 mg, 21.6%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.10 (s, 1H), 7.97 (m, 1H), 7.48 (m, 4H), 6.75 (d,
2H), 5.09 (m, 1H), 3.63 (s, 3H), 3.48 (m, 1H), 3.29 (m, 1H), 3.02
(s, 3H), 1.70-2.30 (m, 6H).
[0375] Enantiomers were separated using a Chiralpak AD
4.6.times.250 mm column, eluting with iPrOH at a flowrate of 2
mL/min, to yield enantiomer 1 as a white foam, 2.6 mg, Rt 6.3 min.
and enantiomer 2 as a white foam, 2.6 mg, Rt 7.1 min.
Example 52
[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methyl-4-
H-[1,2,4]triazol-3-yl)-benzyl]-dimethyl-amine
[0376]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (49.9 mg, 0.1422 mmol) was mixed
with 4-dimethylaminomethyl-benzoic acid hydrazide (30 mg, 0.156
mmol) in ethanol (1.2 mL) at 100.degree. C. overnight. The reaction
mixture was diluted with ethyl acetate, washed with water .times.3,
purified by chromatography with (2.about.3% 2M methanolic ammonia
in chloroform) to give the title compound (9.2 mg, 13.5%) as an
off-white solid. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.09 (s,
1H), 7.98 (m, 1H), 7.60 (d, 2H), 7.45 (m, 4H), 5.11 (m, 1H), 3.66
(s, 3H), 3.48 (s plus m, 3H), 3.30 (m, 1H), 2.28 (s, 6H),
1.60.about.2.20 (m, 6H).
Example 53
{2-[4-(5-{2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-piperidin-1-yl}-4-methy-
l-4H-[1,2,4]triazol-3-yl)-phenoxy]-ethyl}-dimethyl-amine
[0377]
2-[2-(3-Chloro-phenyl)-2H-tetrazol-5-yl]-N-methyl-piperidine-1-car-
boximidothioic acid methyl ester (85 mg, 0.242 mmol) was mixed with
4-(2-dimethylamino-ethoxy)-benzoic acid hydrazide (75.7 mg, 0.339
mmol) in ethanol (1.2 mL) at 100.degree. C. overnight. The reaction
mixture was diluted with dichloromethane, washed with water
(.times.3), purified by chromatography (2.about.3% 2M methanolic
ammonia in chloroform) to give the title compound (32 mg, 26%) as a
yellow sticky oil. .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.09
(s, 1H), 7.97 (m, 1H), 7.56 (d, 2H), 7.44 (m, 2H), 7.01 (d, 2H),
5.09 (m, 1H), 4.11 (t, 2H), 3.62 (s, 3H), 3.65 (m, 1H), 3.44 (m,
1H), 2.76 (t, 2H), 2.36 (s, 6H), 1.60.about.2.30 (m, 6H).
Examples 54a and 54b
(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4--
yl-4H-[1,2,4]triazol-3-yl)-morpholine and
(S)
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4--
yl-4H-[1,2,4]triazol-3-yl)-morpholine
[0378] The two enantiomers were isolated from racemic
3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-4-(4-methyl-5-pyridin-4-yl--
4H-[1,2,4]triazol-3-yl)-morpholine using chiral HPLC column
(Chiralpak AD) with Hexane/Isopropanol (20:80); Enantiomer 1 has
retention time of 7.5 minutes whereas Enantiomer 2 has retention
time of 8.7 minutes.
Examples 55a and 55b
(R)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)pheny-
l]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine
(S)-2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)pheny-
l]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine
[0379]
2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]-1-{5-[4-(difluoromethoxy)p-
henyl]-4-methyl-4H-1,2,4-triazol-3-yl}piperidine was separated by
Chiralpak AD (4.6.times.250) with ethanol:isoproanol (1:1) at 1.0
mL/min flow rate to give two enatiomers 13.3 mg (Rt=14.2 min) and
11.9 mg (Rt=18.7 min).
Examples 56a and 56b
(R)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}-4-methyl--
4H-1,2,4-triazol-3-yl)pyridine
(S)-4-(5-{2-[2-(3-Chlorophenyl)-2H-tetrazol-5-yl]piperidin-1-yl}4-methyl-4-
H-1,2,4-triazol-3-yl)pyridine
[0380] The product was separated by Chiralpak AD (4.6.times.250)
with ethanol:isopropanol (1:1) at 1.0 mL/min flow rate to give two
enatiomers 9.5 mg (Rt=11.6 min) and 10.8 mg (Rt=16.8 min).
Example 57
5-Fluoronicotinohydrazide
[0381] Hydrazine monohydrate 98% (4.9 mL, 101.1 mmol) was added to
a solution of ethyl 5-fluoronicotinate (1.71 g, 10.1 mmol) in EtOH
(35 mL) under argon. The reaction was allowed to stir at room
temperature for five hours. The reaction was concentrated and
triturated with hexane to give the title compound (light yellow
solid, 1.462 g, 93%). .sup.1H NMR CD.sub.3OD .delta. (ppm): 8.82
(s, 1H), 8.65 (m, 1H), 8.01 (dm, 1H).
Example 58
2-Methylisonicotinohydrazide
[0382] HOBt (950 mg, 6.99 mmol), and EDCI (1.34 g, 6.99 mmol) were
added to a suspension of 2-chloro-6-methylisonicotinic acid (1 g,
5.83 mmol) in acetonitrile (15 ml) at room temperature. After 1 h a
solution of hydrazine monohydrate (0.56 ml, 11.66 mmol) and
cyclohexene (0.15 mL, 1.5 mmol) in acetonitrile (5 ml) was added
drop-wise at 0.degree. C. The mixture was stirred overnight and
allowed to warm to room temperature. The solvent was removed in
vacuo and the residue was diluted with ethyl acetate, washed with
saturated sodium bicarbonate and brine, dried over sodium sulfate,
filtered and concentrated to afford
2-chloro-6-methylisonicotinohydrazide (yellow solid, 1.1 g, used
without further purification). A hydrogen filled balloon was
attached to a flask containing
2-chloro-6-methylpyridine-4-carboxylic acid (1.12 g, 6.03 mmol),
palladium 10 wt. % on activated carbon (0.56 g), triethyl amine
(3.4 ml) and ethanol (20 ml) and then stirred overnight at room
temperature. The reaction mixture was filtered through celite,
washed with methanol and concentrated. The residue was triturated
with dichloromethane and then filtered to afford
2-methylisonicotinohydrazide (light yellow solid, crude product
used without further purification).
Example 59
2-Methoxyisonicotinohydrazide
[0383] HOBt (1.73 g, 12.79 mmol), and EDCI (2.45 g, 12.79 mmol)
were added to a suspension of 2-chloro-6-methoxyisonicotinic acid
(2 g, 10.66 mmol) in acetonitrile (25 mL) at room temperature.
After 1 h a solution of hydrazine monohydrate (1.03 ml, 21.32 mmol)
and cyclohexene (0.2 mL, 2.0 mmol) in acetonitrile (5 ml) was added
drop-wise at 0.degree. C. The mixture was stirred overnight and
allowed to warm to room temperature. The solvent was removed in
vacuo and the residue was diluted with ethyl acetate, washed with
saturated sodium bicarbonate and brine, dried over sodium sulfate,
filtered and concentrated to afford
2-chloro-6-methoxyisonicotinohydrazide (light yellow solid, 2.03 g,
95%). A hydrogen filled balloon was attached to a flask containing
2-chloro-6-methylpyridine-4-carboxylic acid (1.83 g, 9.07 mmol),
palladium 10 wt. % on activated carbon (0.91 g), triethyl amine
(5.5 ml) and ethanol (30 ml) and then stirred overnight at room
temperature. The reaction mixture was filtered through celite,
washed with methanol and concentrated. The residue was triturated
with dichloromethane and then filtered to afford
2-methoxyisonicotinohydrazide (light yellow solid, crude product
used without further purification).
Example 60
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-N-methylmorpholine-4-carbothioamid-
e
[0384] To a stirred solution of
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl)morpholine (550 mg, 2.07
mol) in chloroform (8 mL) was added methyl isothiocyanate (227 mg,
3.1 mmol). The solution was stirred at room temperature overnight,
concentrated and triturated with diethyl ether to yield the title
compound as (white solid, 608 mg, 86.7%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. (ppm): 8.13 (s, 1H), 8.03 (dm, 1H), 7.5 (m,
2H), 6.69 (m, 1H), 6.04 (m, 1H), 4.58 (d, 1H), 4.02 (m, 3H), 3.74
(m, 2H), 3.24 (d, 3H).
Example 61
methyl
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-N-methylmorpholine-4-carbim-
idothioate
[0385] To a solution of
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-N-methylmorpholine-4-carbothioami-
d (608 mg, 1.79 mmol) in methanol (12 mL) was added CH.sub.3I (224
.mu.L, 3.59 mmol). The solution was heated to reflux for 1.5 h,
then cooled to room temperature and diluted with dichloromethane
and washed with NaHCO.sub.3 (aq). The aqueous phase was
re-extracted with dichloromethane and the combined organics were
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure to yield the title compound in quantitative yield. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. (ppm): 8.15 (s, 1H), 8.04 (dm,
1H), 7.48 (m, 2H), 5.65 (t, 1H), 4.45 (dd, 1H), 4.03 (dd, 1H), 3.93
(dt, 1H), 3.79 (dm, 1H), 3.72 (td, 1H), 3.59 (tm, 1H), 3.25 (s,
3H), 2.38 (s, 3H).
Example 62
3-(N-Hydroxycarbamimidoyl)-morpholine-4-carboxylic acid tert-butyl
ester
[0386] 3-Cyano-morpholine-4-carboxylic acid tert-butyl ester (600
mg, 2.83 mmol) in methanol (20 mL) was added to a solution of
hydroxylamine hydrochloride (982 mg, 14.13 mmol) and sodium
carbonate (1.498 g, 14.19 mmol) in deionized water (20 mL). The
resulting solution was heated to reflux overnight, then cooled to
room temperature and the methanol was removed in vacuo. The product
was extracted two times with ethyl acetate, then a third time after
adding sodium chloride to saturate the aqueous phase. The solvent
was removed in vacuo to yield the title compound (sticky off-white
solid, 466.8 mg, 67%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
(ppm): 1.50 (s, 9H); 3.23 (td, J=11 Hz, 3 Hz, 1H); 3.55 (m, 2H);
3.81 (m, 2H); 4.58 (s, broad, 1H); 4.92 (s, broad, 1H).
Example 63
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carboxylic
acid tert-butyl ester
[0387] To a stirred solution of
3-(N-hydroxycarbamimidoyl)-morpholine-4-carboxylic acid tert-butyl
ester (300 mg, 1.22 mmol), 3-chloro-benzoic acid (193.4 mg, 1.24
mmol) and HOBt (181.8 mg, 1.35 mmol) in dimethylformamide (4 mL)
was added EDCI (236.8 mg, 1.24 mmol). The solution was stirred
overnight at room temperature, then diluted with dichloromethane
and washed with water. The aqueous phase was re-extracted with
dichloromethane and the combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure. The crude intermediate was filtered through silica gel
using 10% methanol in dichloromethane to remove trace HOBt. The
eluent was concentrated under reduced pressure, then dissolved in
dimethylformamide (3 mL) and heated to 130.degree. C. for 90 min.
Removal of the solvent in vacuo yielded the title compound (300 mg,
67%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. (ppm): 1.51 (s,
9H); 3.54 (m, 3H); 3.89 (m, 2H); 4.51 (m, 2H); 7.47 (m, 1H); 7.58
(m, 1H); 8.02 (m, 2H).
Example 64
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine
[0388] A solution of trifluoroacetic acid (4 mL) in dichloromethane
(2 mL) was added to a solution of
3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carboxylic
acid tert-butyl ester (approx. 200 mg) in dichloromethane (2 mL).
The resulting solution was stirred at room temperature for 30 min,
then diluted with dichloromethane and a small volume of water. The
aqueous phase was neutralized with solid sodium bicarbonate, then
deionized water was added and the organic phase was separated. The
aqueous phase was re-extracted with dichloromethane and the
combined organics were dried, filtered and concentrated under
reduced pressure to yield the title compound (144.9 mg,
quantitative). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. (ppm):
3.10 (m, 2H); 3.72 (m, 1H); 3.85 (m, 2H); 4.18 (dd, J=11 Hz, 3 Hz,
1H); 4.27 (dd, J=8 Hz, 3 Hz, 1H); 7.49 (t, J=8 Hz, 1H); 7.60 (m,
1H); 8.04 (m, 2H).
Example 65
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carbothioicacid
methylamide
[0389] To a stirred solution of
3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine (184.8 mg,
0.696 mol) in chloroform (5 mL) was added methyl isothiocyanate
(54.7 .mu.L, 0.800 mmol). The solution was stirred at room
temperature overnight, diluted with dichloromethane and washed with
water. The aqueous phase was re-extracted with dichloromethane and
the combined organics were dried (Na.sub.2SO.sub.4) filtered and
concentrated under reduced pressure. The crude product was
chromatographed in 60% ethyl acetate in hexanes to yield the title
compound as off-white crystals. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. (ppm): 3.06 (d, J=4.2 Hz, 3H); 3.61 (quintet of d, J=12 Hz,
3 Hz, 2H); 3.92 (m, 3H); 4.51 (d, J=12 Hz, 1H); 6.51 (s, broad,
2H); 7.42 (t, J=7.5 Hz, 1H); 7.51 (m, 1H); 7.92 (m, 1H); 8.01 (m,
1H).
Example 66
3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-N-methyl-morpholine-4-carbox-
imidothioc acid methyl ester
[0390] To a solution of
3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-morpholine-4-carbothioic
acid methylamide (137.6 mg, 0.41 mmol) in methanol (3 mL) was added
CH.sub.3I (50.6 .mu.L, 0.82 mmol). The solution was heated to
reflux for 1.5 h, then cooled to room temperature and diluted with
dichloromethane and washed with NaHCO.sub.3 (aq). The aqueous phase
was re-extracted with dichloromethane and the combined organics
were dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure to yield the title compound in quantitative yield.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. (ppm): 2.34 (s, 3H); 3.24
(s, 3H); 3.61 (quintuplet of d, J=12 Hz, 3.3 Hz, 2H); 3.80 (d, J=12
Hz, 1H); 3.91 (m, 2H); 4.40 (dd, J=12 Hz, 2 Hz, 1H); 5.46 (s,
broad, 1H); 7.43 (t, J=8.1 Hz, 1H); 7.52 (m, 1H); 7.96 (d, J=7.5
Hz, 1H); 8.07 (m, 1H).
Example 67
tert-Butyl
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]morpholine-4-carboxyla-
te
[0391] Isobutyl chloroformate (1.56 mL, 12.0 mmol) was added to a
solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester
(2.528 g, 10.9 mmol) and triethylamine (3.8 mL, 27.3 mmol) in THF
(35 mL) at 0.degree. C. and the mixture was stirred for 2 hours.
3-Iodo-N-hydroxy-benzamidine (2.86 g, 10.9 mmol) was added and the
mixture was stirred 1 h at room temperature, and the solvent was
removed in vacuo. The acyclic ester intermediate was used without
further purification. DMF (25 mL) was added and the mixture was
heated at 120.degree. C. overnight. The product was extracted into
ethyl acetate and the organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. Chromatography (silica gel, 10-20% ethyl
acetate in hexane) yielded the title compound (light yellow oil,
3.0403 g, 61%) which appeared as a mixture of rotomers in the NMR.
.sup.1H NMR (CDCl.sub.3) (ppm): 8.44 (s, 1H), 8.06 (d, 1H), 7.85
(d, 1H), 7.23 (t, 1H), 5.41 (br s, 0.5H), 5.24 (br s, 0.5H), 4.52
(br s, 1H), 3.9 (m, 3H), 3.6 (t, 1H), 3.49 (m, 1H), 1.53 (s, 4.5H),
1.46 (s, 4.5H).
Example 68
3-[3-(3-Iodophenyl)-1,2,4-oxadiazol-5-yl]morpholine
[0392] A solution of trifluoroacetic acid (9.6 mL) in
dichloromethane (25 mL) was added to a solution tert-butyl
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]morpholine-4-carboxylate
(3.04 g, 6.05 mmol) in dichloromethane (30 mL) and the mixture was
stirred at room temperature overnight and concentrated to dryness.
The residue was dissolved in ethyl acetate and washed with sodium
hydroxide (1N aqueous, 15 mL). The organic phase was washed with
brine, dried (sodium sulfate), filtered and concentrated in vacuo.
Chromatography (silica gel, 5% 2M methanolic ammonia in
dichloromethane) yielded the title compound (yellow oil, 2.1599 g,
91%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.48 (s, 1H), 8.08
(d, 1H), 7.86 (d, 1H), 7.24 (t, 1H), 4.34 (m, 1H), 4.2 (d, 1H),
3.86-3.99 (m, 2H), 3.74 (t, 1H), 3.18 (d, 1H), 3.05 (t, 1H).
Example 69
3-[3-(3-Iodophenyl)-1,2,4-oxadiazol-5-yl]-N-methylmorpholine-4-carbothioam-
ide
[0393] Methyl isothiocyanate (575 mg, 7.86 mmol) was added to
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]morpholine (2.16 g, 6.05
mmol) in CHCl.sub.3 (50 mL) and the resulting mixture was stirred
at 60.degree. C. for 7 h and left at room temperature weekend. The
mixture was concentrated in vacuo and the isolated residue was
triturated with diethyl ether in hexanes to isolate the title
compound (yellow oil, 2.6 g, 100%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 8.38 (s, 1H), 8.02 (d, 1H), 7.83 (d, 1H), 7.2 (t,
1H), 6.86 (m, 1H), 6.18 (m, 1H), 4.56 (d, 1H), 3.99 (m, 2H), 3.78
(t, 2H), 3.63 (m, 1H), 3.03 (d, 3H).
Example 70
Methyl
3-[3-(3-iodophenyl)-1,2,4-oxadiazol-5-yl]-N-methylmorpholine-4-carb-
imidothioate
[0394] Iodomethane (0.11 mL, 1.74 mmol) was added to
3-[3-(3-Iodophenyl)-1,2,4-oxadiazol-5-yl]-N-methylmorpholine-4-carbothioa-
mide (465 mg, 1.08 mmol) in methanol (5 mL) and the resulting
mixture was stirred at 75.degree. C. for 4 h. The mixture was
cooled to room temperature, concentrated in vacuo, diluted with
saturated sodium bicarbonate (aqueous), extracted with
dichloromethane. The combined organic phase was dried (sodium
sulfate), filtered and concentrated in vacuo to yield the title
compound as yellow oil (460 mg, 96%). .sup.1H NMR (CDCl.sub.3),
.delta. (ppm): 7.44 (s, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.22 (t,
1H), 5.46 (m, 1H), 4.36 (dm, 1H), 3.96 (m, 2H), 3.65-3.86 (m, 3H),
3.22 (s, 3H), 2.37 (s, 3H).
Example 71
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid
tert-butyl ester
[0395] A solution of 2-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (4.2 g, 21.1 mmol) (Available from PharmaCore,
Inc., 4180 Mendenhall Oaks Parkway, Suite 160, High Point, N.C.
27265, USA or synthesized according to procedure by Beak et. al. J.
Org. Chem. 1993, 58, 1109) in dry pyridine (8 mL) was added to an
ice-cold solution of hydroxylamine hydrochloride (1.90 g, 27.4
mmol) in dry pyridine (25 mL). The solution was stirred at room
temperature overnight. Water (500 mL) was added and the solution
was extracted with dichloromethane (3.times.200 mL). The combined
organic layers were washed with brine, dried (sodium sulfate),
filtered and concentrated in vacuo. The residue was dissolved in
dry DMF (50 mL) and heated to 40.degree. C. A solution of
N-chlorosuccinimide (3.10 g, 23.2 mmol) in dry DMF (30 mL) was
added and the reaction was stirred at 40.degree. C. for 1.5 h and
then at room temperature overnight. A further 844 mg (6.3 mmol) of
N-chlorosuccinimide was added and the reaction was stirred at
40.degree. C. for 1.5 h. The reaction mixture was allowed to cool
and was diluted with diethyl ether (500 mL) and washed with water
(3.times.300 mL) followed by brine (100 mL). The organic layer was
dried (sodium sulfate), filtered and concentrated in vacuo. The
residue was dissolved in dry dichloromethane (30 mL) and added to
an ice-cold solution of 1-Chloro-3-ethynyl-benzene and
triethylamine in dry dichloromethane (25 mL). The reaction was
stirred overnight at room temperature and the solvent was removed
in vacuo. The residue was dissolved in ethyl acetate (300 mL) and
washed with water (3.times.100 mL) and brine (100 mL). The organic
layer was dried (sodium sulfate), filtered and concentrated in
vacuo. The residue was purified by flash chromatography
(heptane:ethyl acetate 8:1-4:1) to give the title compound (3.48 g,
48%) as an oil which solidified on standing. .sup.1H NMR (400 MHz,
CDCl.sub.3, rotamers) .delta. (ppm): 1.10-1.69 (m, 9H); 1.71-2.44
(m, 4H); 3.34-3.68 (m, 2H); 4.90-5.10 (m, 1H); 6.40-6.55 (m, 1H);
7.37 (bs, 2H); 7.67 (m, 1H); 7.72 (bs, 1H).
Example 72
5-(3-Chloro-phenyl)-3-pyrrolidin-2-yl-isoxazole
[0396]
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid
tert-butyl ester (3.45 g, 9.9 mmol) was dissolved in
dichloromethane (15 mL) and trifluoroacetic acid (15 mL) was added.
The solution was stirred at room temperature for 1 h and then
concentrated in vacuo. The residue was dissolved in dichloromethane
(200 mL) and washed with 1 M aqueous NaOH (200 mL). The aqueous
layer was extracted with dichloromethane (2.times.100 mL) and the
combined organic layers were washed with water (100 mL) and brine
(100 mL), dried (sodium sulfate), filtered and concentrated in
vacuo to give the title compound (2.12 g, 86%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. (ppm): 1.88 (m, 3H); 2.1 (s, 1H); 3.62 (m,
1H); 3.12 (m, 1H); 4.32 (dd, 1H); 6.51 (s, 1H); 7.35 (m, 1H); 7.61
(m, 1H); 7.72 (s, 1H).
Example 73
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carbothioic
acid methylamide
[0397] Methylisothiocyanate (329 mg, 4.5 mmol) was added to
5-(3-chloro-phenyl)-3-pyrrolidin-2-yl-isoxazole (746 mg, 3.0 mmol)
in dry dichloromethane (20 mL) at room temperature. The reaction
was stirred overnight and concentrated in vacuo. The residue was
purified by flash chromatography using a gradient of 20-80% ethyl
acetate in heptane to give the title compound (580 mg, 60%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 2.21 (m, 3H); 2.37
(m, 1H); 3.11 (d, 3H); 3.79 (m, 2H); 5.53 (bs, 1H); 6.57 (s, 1H);
7.39 (m, 1H), 7.68 (m, 1H); 7.73 (m, 1H).
Example 74
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carbothioic
acid cyclopropylamide
[0398] Cyclopropylisothiocyanate (446 mg, 4.5 mmol) was added to
5-(3-chloro-phenyl)-3-pyrrolidin-2-yl-isoxazole (746 mg, 3.0 mmol)
in dry dichloromethane (20 mL) at room temperature. The reaction
was stirred overnight and concentrated in vacuo. The residue was
purified by flash chromatography using a gradient of 20-80% ethyl
acetate in heptane to give the title compound (585 mg, 56%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 0.55 (m, 2H); 0.83
(m, 2H); 2.20 (m, 3H); 2.39 (m, 1H); 3.03 (m, 1H); 3.80 (m, 2H);
5.45 (bs, 1H); 5.87 (bs, 1H); 6.65 (bs, 1H); 7.40 (m, 2H); 7.64 (m,
1H); 7.75 (bs, 1H).
Example 75
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-methyl-pyrrolidine-1-carboximidoth-
ioic acid methyl ester
[0399] A suspension of
2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carbothioic
acid methylamide (520 mg, 1.61 mmol) and methyl iodide (344 mg,
2.42 mmol) in dry methanol (10 mL) was heated by single-node
microwave irradiation in a sealed vessel at 110.degree. C. for 15
min. After cooling, the resulting solution was diluted with
saturated aqueous sodium bicarbonate (50 mL) and extracted with
dichloromethane (3.times.70 mL). The combined organic layers were
washed with brine, dried (sodium sulfate), filtered and
concentrated in vacuo to give the title compound as an oil (533 mg,
98%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 2.00 (m,
3H); 2.12 (m, 1H); 2.26 (s, 3H); 3.23 (s, 3H); 3.63 (m, 1H); 3.71
(m, 1H); 5.39 (m, 1H); 6.39 (s, 1H); 7.37 (m, 2H); 7.63 (m, 1H);
7.72 (bs, 1H).
Example 76
a)
2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-N-cyclopropyl-pyrrolidine-1-carbo-
ximidothioic acid methyl ester
[0400] A suspension of
2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-pyrrolidine-1-carbothioic
acid cyclopropylamide (546 mg, 1.57 mmol) and methyl iodide (335
mg, 2.36 mmol) in dry methanol (10 mL) was heated by single-node
microwave irradiation in a sealed vessel at 75.degree. C. for 2 h.
After cooling, the resulting solution was diluted with saturated
aqueous sodium bicarbonate (40 mL) and extracted with
dichloromethane (3.times.50 mL). The combined organic layers were
washed with brine, dried (sodium sulfate), filtered and
concentrated in vacuo to give the title compound as an oil (563 mg,
99%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 0.51 (m,
1H); 0.60 (m, 1H); 0.69 (m, 2H); 1.96 (m, 2H); 2.12 (m, 1H); 2.29
(m, 1H); 2.33 (m, 3H); 3.10 (m, 1H); 3.59 (m, 1H); 3.66 (m, 1H);
5.28 (m, 1H); 6.37 (s, 1H); 7.35 (m, 2H); 7.61 (m, 1H); 7.70 (bs,
1H).
[0401] The following compounds were prepared in a similar
manner:
[0402] b)
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-
-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine;
yield 24 mg, 23%, off-white solid; .sup.1H NMR CDCl.sub.3 (500
MHz):8.54 (d, 1H), 7.92 (dd, 1H), 7.70 (s, 1H), 7.59 (m, 1H), 7.38
(m, 2H), 6.67 (d, 1H), 6.50 (s, 1H), 5.54 (dd, 1H), 4.06 (ddd, 1H),
3.83 (m, 4H), 3.61 (m, 1H), 3.58 (m, 4H), 3.21 (m, 1H), 2.54 (m,
1H), 2.29 (m, 1H), 2.21 (m, 1H), 2.14 (m, 1H), 1.11 (m, 2H), 0.99
(m, 1H), 0.52 (m, 1H)
[0403] c)
4-[5-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-
-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-yl]-morpholine; yield
41 mg, 34%, light-yellow solid; .sup.1H NMR CDCl.sub.3 (500 MHz):
8.38 (d, 1H), 7.81 (dd, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.37 (m,
2H), 6.70 (d, 1H), 6.59 (s, 1H), 5.41 (t, 1H), 3.87 (m, 1H), 3.83
(m, 4H), 3.59 (m, 4H), 3.52 (m, 4H), 2.55 (m, 1H), 2.30 (m, 1H),
2.19 (m, 2H)
[0404] d)
3-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4--
methyl-4H-[1,2,4]triazol-3-yl)-pyridine; yield 72 mg, 64%,
off-white solid; .sup.1H NMR CDCl.sub.3 (500 MHz): 8.84 (d, 1H),
8.68 (dd, 1H), 8.01 (dt, 1H), 7.71 (m 1H), 7.61 (m, 1H), 7.42 (dd,
1H), 7.37 (m, 2H), 6.54 (s, 1H), 5.42 (dd, 1H), 3.90 (dt, 1H), 3.57
(s, 3H), 3.54 (ddd, 1H), 2.56 (dddd, 1H), 2.24 (m, 3H)
[0405] e)
4-(5-{2-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-pyrrolidin-1-yl}-4--
cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine; yield 75 mg, 68%,
off-white solid; .sup.1H NMR CDCl.sub.3 (500 MHz): 8.69 (dd, 2H),
7.70 (m, 3H), 7.59 (m, 1H), 7.36 (m, 2H), 6.52 (s, 1H), 5.58 (dd,
1H), 4.11 (dt, 1H), 3.66 (m, 1H), 3.32 (m, 1H), 2.57 (m, 1H), 2.26
(m, 3H), 2.16 (m, 1H), 1.15 (m, 2H), 1.00 (m, 1H), 0.47 (m, 1H)
Example 77
4-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-methyl-4H-1,2,-
4-triazol-3-yl)pyridine
[0406] A suspension of
2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-methyl-pyrrolidine-1-carboximidot-
hioic acid methyl ester (61 mg, 0.18 mmol), isonicotinic acid
hydrazide (43.2 mg, 0.32 mmol) and pyridine (18 mg, 0.23 mmol) in
ethanol (3 mL) was heated by single-node microwave irradiation in a
sealed vial at 130.degree. C. After cooling, the solvent was
evaporated and the residue was purified by reversed-phase HPLC
using a linear gradient of acetonitrile in 0.15% aqueous
trifluoroacetic acid. A second purification by reversed-phase HPLC
using a linear gradient of acetonitrile in 0.1 M aqueous ammonium
acetate to gave the title compound (18.5 mg, 25%) as a white solid
after freeze-drying. .sup.1H NMR CDCl.sub.3 (500 MHz) .delta.
(ppm): 8.71 (d, 2H), 7.69 (s, 1H), 7.58 (m, 3H), 7.36 (m, 2H), 6.53
(s, 1H), 5.42 (dd, 1H), 3.91 (dt, 1H), 3.60 (s, 3H), 3.54 (ddd,
1H), 2.56 (m, 1H), 2.23 (m, 3H)
Example 78
3-(5-{2-[5-(3-chlorophenyl)isoxazol-3-yl]pyrrolidin-1-yl}-4-cyclopropyl-4H-
-1,2,4-triazol-3-yl)pyridine
[0407] A suspension of
2-[5-(3-chloro-phenyl)-isoxazol-3-yl]-N-cyclopropyl-pyrrolidine-1-carboxi-
midothioic acid methyl ester (76 mg, 0.21 mmol), nicotinic acid
hydrazide (43.2 mg, 0.32 mmol) and pyridine (18 mg, 0.23 mmol) in
2.5 ml of 2-propanol was heated by single-node microwave
irradiation in a sealed vial at 150.degree. C. After cooling, the
solvent was evaporated and the residue was purified by
reversed-phase HPLC using a linear gradient of acetonitrile in 0.1
M aqueous ammonium acetate to give the title compound (50.3 mg,
55%) as an off-white solid after freeze-drying. .sup.1H NMR
CDCl.sub.3 (500 MHz) .delta. (ppm): 9.00 (d, 1H), 8.65 (dd, 1H),
8.13 (dt, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.38 (m, 3H), 6.53 (s,
1H), 5.58 (dd, 1H), 4.11 (dt, 1H), 3.65 (ddd, 1H), 3.31 (m, 1H),
2.56 (m, 1H), 2.26 (m, 2H), 2.16 (m, 1H), 1.14 (m, 2H), 0.98 (m,
1H), 0.44 (m, 1H).
Example 79
a)
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-4-yl-4H-1-
,2,4-triazol-3-yl)morpholine
[0408] Isonicotinic acid hydrazide (155.5 mg, 1.13 mmol) was added
to methyl
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-N-methylmorpholine-4-carbi-
midothioate (200 mg, 0.567 mmol) in isopropanol (4 mL). The mixture
was stirred at 85-95.degree. C. overnight, and then diluted with
dichloromethane (8 mL). The organic phase was sequentially washed
with water and brine, dried, filtered and concentrated in vacuo.
Trituration with diethyl ether yielded the title compound (white
solid, 212 mg, 88%). .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.76
(d, 2H), 8.1 (s, 1H), 7.99 (m, 1H), 7.62 (m, 2H), 7.48 (m, 2H), 5.2
(dd, 1H), 4.32 (dd, 1H), 4.12 (m, 2H), 4.03 (m, 1H), 3.77 (s, 3H),
3.6 (m, 1H), 3.42 (m, 1H).
[0409] The following compounds were prepared in a similar
manner:
[0410] b)
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-(4-methyl-5-pyridin-3-
-yl-4H-1,2,4-triazol-3-yl)morpholine; yield 89.3 mg, 87.4% white
solid; .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.89 (s, 1H), 8.73
(d, 1H), 8.11 (m, 1H), 8.03 (m, 2H), 7.47 (m, 3H), 5.2 (dd, 1H),
4.33 (dd, 1H), 4.12 (m, 2H), 4.04 (m, 1H), 3.74 (s, 3H), 3.59 (m,
1H), 3.46 (m, 1H)
[0411] c)
3-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-4-[5-(3,5-difluoropheny-
l)-4-methyl-4H-1,2,4-triazol-3-yl]morpholine; yield 78.9 mg, 71.4%
white solid; .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.1 (s, 1H),
7.99 (m, 1H), 7.48 (m, 2H), 7.23 (m, 2H), 6.94 (tm, 1H), 5.18 (dd,
1H), 4.32 (dd, 1H), 4.11 (m, 2H), 4.02 (m, 1H), 3.73 (s, 3H), 3.57
(dm, 1H), 3.41 (m, 1H)
Pharmacology
[0412] The pharmacological properties of the compounds of the
invention can be analyzed using standard assays for functional
activity. Examples of glutamate receptor assays are well known in
the art as described in for example Aramori et al., Neuron 8:757
(1992), Tanabe et al., Neuron 8:169 (1992), Miller et al., J.
Neuroscience 15: 6103 (1995), Balazs, et al., J. Neurochemistry
69:151 (1997). The methodology described in these publications is
incorporated herein by reference. Conveniently, the compounds of
the invention can be studied by means of an assay that measures the
mobilization of intracellular calcium, [Ca.sup.2++].sub.i in cells
expressing mGluR5.
[0413] For FLIPR analysis, cells expressing human mGluR5d as
described in WO97/05252 were seeded on collagen coated clear bottom
96-well plates with black sides and analysis of [Ca.sup.2+].sub.i
mobilization was done 24 h after seeding.
[0414] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed. Each FLIPR experiment
was initiated with 160 .mu.l of buffer present in each well of the
cell plate. After each addition of the compound, the fluorescence
signal was sampled 50 times at 1 second intervals followed by 3
samples at 5 second intervals. Responses were measured as the peak
height of the response within the sample period. EC.sub.50 and
IC.sub.50 determinations were made from data obtained from 8-point
concentration response curves (CRC) performed in duplicate. Agonist
CRC were generated by scaling all responses to the maximal response
observed for the plate. Antagonist block of the agonist challenge
was normalized to the average response of the agonist challenge in
14 control wells on the same plate.
[0415] We have validated a secondary functional assay for mGluR5d
as described in WO97/05252 based on Inositol Phosphate (IP.sub.3)
turnover. IP.sub.3 accumulation is measured as an index of receptor
mediated phospholipase C turnover. GHEK cells stably expressing the
human mGluR5d receptors were incubated with [3H] myo-inositol
overnight, washed three times in HEPES buffered saline and
pre-incubated for 10 min with 10 mM LiCl. Compounds (agonists) were
added and incubated for 30 min at 37.degree. C. Antagonist activity
was determined by pre-incubating test compounds for 15 min, then
incubating in the presence of glutamate (80 .mu.M) or DHPG (30
.mu.M) for 30 min. Reactions were terminated by the addition of
perchloric acid (5%). Samples were collected and neutralized, and
inositol phosphates were separated using Gravity-Fed Ion-Exchange
Columns.
[0416] A detailed protocol for testing the compounds of the
invention is provided in the assay below.
Assay of Group I Receptor Antagonist Activity
[0417] For FLIPR analysis, cells expressing human mGluR5d as
described in WO97/05252 were seeded on collagen coated clear bottom
96-well plates with black sides and analysis of [Ca.sup.2+].sub.i
mobilization was performed 24 h following seeding. Cell cultures in
the 96-well plates were loaded with a 4 .mu.M solution of
acetoxymethyl ester form of the fluorescent calcium indicator
fluo-3 (Molecular Probes, Eugene, Oreg.) in 0.01% pluronic. All
assays were performed in a buffer containing 127 mM NaCl, 5 mM KCl,
2 mM MgCl.sub.2, 0.7 mM NaH.sub.2PO.sub.4, 2 mM CaCl.sub.2, 0.422
mg/ml NaHCO.sub.3, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml
BSA Fraction IV (pH 7.4).
[0418] FLIPR experiments were done using a laser setting of 0.800 W
and a 0.4 second CCD camera shutter speed with excitation and
emission wavelengths of 488 nm and 562 nm, respectively. Each FLIPR
experiment was initiated with 160 .mu.l of buffer present in each
well of the cell plate. A 40 .mu.l addition from the antagonist
plate was followed by a 50 .mu.L addition from the agonist plate.
After each addition the fluorescence signal was sampled 50 times at
1 second intervals followed by 3 samples at 5 second intervals.
Responses were measured as the peak height of the response within
the sample period.
[0419] EC.sub.50/IC.sub.50 determinations were made from data
obtained from 8 points concentration response curves (CRC)
performed in duplicate. Agonist CRC were generated by scaling all
responses to the maximal response observed for the plate.
Antagonist block of the agonist challenge was normalized to the
average response of the agonist challenge in 14 control wells on
the same plate.
Measurement of Inositol Phosphate Turnover in Intact Whole
Cells
[0420] GHEK stably expressing the human mGluR5d receptor were
seeded onto 24 well poly-L-lysine coated plates at
40.times.10.sup.4 cells/well in media containing 1 .mu.Ci/well [3H]
myo-inositol. Cells were incubated overnight (16 h), then washed
three times and incubated for 1 h at 37.degree. C. in HEPES
buffered saline (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl.sub.2, 0.1%
glucose, 20 mM HEPES, pH 7.4) supplemented with 1 unit/ml glutamate
pyruvate transaminase and 2 mM pyruvate. Cells were washed once in
HEPES buffered saline and pre-incubated for 10 min in HEPES
buffered saline containing 10 mM LiCl. Compounds (agonists) were
added and incubated at 37.degree. C. for 30 min. Antagonist
activity was determined by pre-incubating test compounds for 15
min, then incubating in the presence of glutamate (80 .mu.M) or
DHPG (30 .mu.M) for 30 min. The reaction was terminated by the
addition of 0.5 ml perchloric acid (5%) on ice, with incubation at
4.degree. C. for at least 30 min. Samples were collected in 15 ml
Falcon tubes and inositol phosphates were separated using Dowex
columns, as described below.
Assay for Inositol Phosphates Using Gravity-Fed Ion-Exchange
Columns
Preparation of Ion-Exchange Columns
[0421] Ion-exchange resin (Dowex AG 1-X8 formate form, 200-400
mesh, BIORAD) was washed three times with distilled water and
stored at 4.degree. C. 1.6 ml resin was added to each column, and
washed with 3 ml 2.5 mM HEPES, 0.5 mM EDTA, pH 7.4.
a) Sample Treatment
[0422] Samples were collected in 15 ml Falcon tubes and neutralized
with 0.375 M HEPES, 0.75 M KOH. 4 ml of HEPES/EDTA (2.5/0.5 mM, pH
7.4) were added to precipitate the potassium perchlorate.
Supernatant was added to the prepared Dowex columns.
b) Inositol Phosphate Separation
[0423] Elute glycero phosphatidyl inositols with 8 ml 30 mM
ammonium formate. Elute total inositol phosphates with 8 ml 700 mM
ammonium formate/100 mM formic acid and collect eluate in
scintillation vials. Count eluate mixed with 8 ml scintillant.
[0424] One aspect of the invention relates to a method for
inhibiting activation of mGluR5, comprising treating a cell
containing said receptor with an effective amount of the compound
of formula I.
Screening for Compounds Active Against tlesr
[0425] Adult Labrador retrievers of both genders, trained to stand
in a Pavlov sling, are used. Mucosa-to-skin esophagostomies are
formed and the dogs are allowed to recover completely before any
experiments are done.
Motility Measurement
[0426] In brief, after fasting for approximately 17 h with free
supply of water, a multilumen sleeve/sidehole assembly (Dentsleeve,
Adelaide, South Australia) is introduced through the esophagostomy
to measure gastric, lower esophageal sphincter (LES) and esophageal
pressures. The assembly is perfused with water using a
low-compliance manometric perfusion pump (Dentsleeve, Adelaide,
South Australia). An air-perfused tube is passed in the oral
direction to measure swallows, and an antimony electrode monitored
pH, 3 cm above the LES. All signals are amplified and acquired on a
personal computer at 10 Hz.
[0427] When a baseline measurement free from fasting gastric/LES
phase III motor activity has been obtained, placebo (0.9% NaCl) or
test compound is administered intravenously (i.v., 0.5 ml/kg) in a
foreleg vein. Ten min after i.v. administration, a nutrient meal
(10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) is infused into
the stomach through the central lumen of the assembly at 100 ml/min
to a final volume of 30 ml/kg. The infusion of the nutrient meal is
followed by air infusion at a rate of 500 ml/min until an
intragastric pressure of 10.+-.1 mmHg is obtained. The pressure is
then maintained at this level throughout the experiment using the
infusion pump for further air infusion or for venting air from the
stomach. The experimental time from start of nutrient infusion to
end of air insufflation is 45 min. The procedure has been validated
as a reliable means of triggering TLESRs.
[0428] TLESRs is defined as a decrease in lower esophageal
sphincter pressure (with reference to intragastric pressure) at a
rate of >1 mmHg/s. The relaxation should not be preceded by a
pharyngeal signal <2 s before its onset in which case the
relaxation is classified as swallow-induced. The pressure
difference between the LES and the stomach should be less than 2
mmHg, and the duration of the complete relaxation longer than 1
s.
Abbreviations
[0429] BSA Bovine Serum Albumin [0430] CCD Charge Coupled Device
[0431] CRC Concentration Response Curve [0432] DHPG
3,5-dihydroxyphenylglycine; [0433] EDTA Ethylene Diamine
Tetraacetic Acid [0434] FLIPR Fluorometric Imaging Plate reader
[0435] GHEK GLAST-containing Human Embrionic Kidney [0436] GLAST
glutamate/aspartate transporter [0437] HEPES
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (buffer) [0438]
IP.sub.3 inositol triphosphate Results
[0439] Typical IC.sub.50 values as measured in the assays described
above are 10 .mu.M or less. In one aspect of the invention the
IC.sub.50 is below 2 .mu.M. In another aspect of the invention the
IC.sub.50 is below 0.2 .mu.M. In a further aspect of the invention
the IC.sub.50 is below 0.05 .mu.M. TABLE-US-00001 Compound FLIPR
IC.sub.50 3-[3-(3-chlorophenyl)-1,2,4-oxadiazole-5-yl]4- 199 nM
{5-[4-(difluoromethoxy)phenyl]-4-methyl-4H-
1,2,4-triazole-3-yl}morpholine
4-(5-{2-[2-(3-chlorophenyl)-2H-tetrazole-5- 40 nM
yl]piperidin-1-yl}-4-methyl-4H-1,2,4-triazole- 3-yl)pyridine
* * * * *